FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
1. Title of the invention
"Process for preparation of Trimetazidine and pharmaceutically acceptable salt thereof."
2. Applicant(s)
Name Nationality Address
USV LIMITED Indian company incorporated B. S. D. Marg, Station Road, Govandi, Mumbai-400 088,
under Companies Act, 1956 Maharashtra India.
3. Preamble to the description
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 industrial process for the preparation of Trimetazidine or pharmaceutically acceptable salts thereof, particularly Trimetazidine dihydrochloride.
Background of the invention:
The compound l-(2,3,4-trimethoxybenzyl)-piperazine dihydrochloride also known as Trimetazidine dihydrochloride (I), developed by Servier is indicated for management of angina pectoris and is also used in the management of certain disorders of ischaemic origin. It is used therapeutically as a coronary vasodilator for the prophylactic treatment of anginal chest pain attack and during such attacks, during chorioretinal attacks as well as for the treatment of giddiness of vascular origin (Vertigo of Maniere, acouphenous).

It is first in the new class of metabolic agents known as the 3-KAT(3-ketoacyl CoA thiolase) inhibitors which optimizes cardiac metabolism and prevents deleterious consequences of myocardial ischemia, leading to symptom relief and improvement in exercise test parameters.
Trimetazidine dihydrochloride is marketed under the brand names, Vastarel MR, Cardaptan, Idaptan, Preductal, Flavedon, Trizedon, Vastinan or Vasorel. It is administered orally in doses of 40 to 60mg daily in divided doses as immediate release preparation. Vastarel MR contains 35mg of Trimetazidine dihydrochloride and is administered twice daily.
FR805M discloses a process for preparing l-(2,3,4-trimethoxybenzyl) piperazine

comprising condensation of 2,3,4-trimethoxybenzyl chloride with 1 -formyl piperazine to obtain the condensed product (II) which is hydrolysed to get Trimetazidine which is subsequently converted to its hydrochloride salt. The reaction sequence of this process is represented below in Scheme I,

There are various processes for preparation of trialkoxylated 1-benzylpiperazine compounds. French Patent 1302958 discloses various processes for preparation of trialkoxylated 1-benzylpiperazine compounds, and in particular 1-(2,3,4-trimethoxybenzyl)-piperazine. The process comprises condensation of 2,3,4-trimethoxybenzyl chloride and 1-formylpiperazine to obtain the condensed product, which is then hydrolyzed to obtain Trimetazidine. This process which involves the use of N-formyl piperazine as raw material produces Trimetazidine in low yield.
The processes for the preparation of l-(2,3,4-trimethoxybenzyl)piperazine (Trimetazidine) reported in the prior art are multi-step synthesis and result in low yield of about 43%.

JP48032889 describes process for the preparation of Trimetazidine from 2,3,4-trimethoxybenzaldehyde and hexahydrated piperazine. The reaction is carried out at 80°C to 90°C in the presence of formic acid for 10 to 18 hours and the yield is in the range of 38%.
Another process for the preparation of l-(trialkoxybenzyl)piperazine compounds is described in FR2493316. The process is characterised in that a suitable 2-piperazinone derivative is prepared in a first step by reaction of a suitably substituted trialkoxybenzyl chloride with 2-piperazinone followed by reduction of obtained piperazinone derivative in the second step using reducing agent preferably LiAlH4 or B2H6 to get the desired compound. This process necessarily entails the preparation of piperazin-2-one, which is not a commercial product.
US5142053 describes process for preparation of Trimetazidine dihydrochloride which comprises dissolving 2,3,4-trimethoxybenzaldehyde together with an excess of piperazine in an alcoholic solvent or in methyl tert-butyl ether; subjecting the obtained solution to the action of hydrogen, in the presence of a hydrogenation catalyst; separating the excess piperazine and isolating Trimetazidine base; and converting Trimetazidine into its addition salts with a pharmaceutically acceptable organic or mineral acid.
Following the above process, the product obtained contains dimer impurity, (1,4-bis (2,3,4-Trimethoxybenzyl)piperazine) in the range of 4-6% which does not meet the ICH requirement.

l,4-bis(2,3,4-Trimethoxybenzyl)piperazine Further this process requires two purification steps to get pure compound or ICH

passing material, thus not suitable on an industrial scale. The overall yield of this process is only 48%.
CN101575321 discloses the preparation of Trimetazidine hydrochloride which comprises, adding a solvent, 2,3,4-trimethoxy benzaldehyde and piperazine with the molar ratio of 1:1 to 1:3 and a nickel-based catalyst, accounting for 3 to 10% of the mass percentage of the 2,3,4-trimethoxy benzaldehyde and anhydrous piperazine, to a pressure kettle using nitrogen for purging before hydrogen is led in, with hydrogen pressure maintained within range of 0.7MPa to 2.0MPa, reaction temperature within range of 50° to 95° C, reaction time within the range of 4 hours to 10 hours, pH value regulated to 3 to 4; separating out organic phase; and recovering the solvent. The water phase is washed with chlorinated hydrocarbon extraction, and the pH value is regulated to 12, then the water phase is extracted with aromatic hydrocarbon, and the aromatic hydrocarbon in the aromatic hydrocarbon extraction liquid is steamed out, thus obtaining Trimetazidine. Trimetazidine is further dissolved in low grade alcohol or ether solvent and reacted with concentrated hydrochloric acid solution to obtain Trimetazidine hydrochloride.
It is found that the reaction does not proceed to completion when nickel based catalyst is used for the hydrogenation reaction. Besides, pH adjustment of 3 to 4 during work up generates impurities which makes' it necessary to purify the final product.
In view of the processes for preparation of Trimetazidine dihydrochloride as discussed in the art, there exists a need to provide a simple, consistent, ecofriendly, robust and commercially viable process for the preparation of substantially pure Trimetazidine dihydrochloride. The process of the present invention involves the use of a solvent system which enables smooth reaction, easy work up, minimizes impurities thereby providing the product in high yield and purity.

Object of the invention:
An object of the present invention is to provide a simple, consistent, cost effective, readily scalable and robust process for preparation of Trimetazidine and pharmaceutically acceptable salts thereof, in particular, Trimetazidine dihydrochloride.
Another object of the present invention is to provide substantially pure Trimetazidine dihydrochloride having purity of more than 99.8 %, without the need for further purification.
Summary of the invention:
According to one aspect of the present invention, there is provided a process for preparation of Trimetazidine or pharmaceutically acceptable salts thereof comprising,
a) treating 2,3,4-trimethoxy benzaldehyde with piperazine in a mixture of hydrocarbon and alcohol in presence of a hydrogenating agent to get a reaction mixture containing Trimetazidine;
b) optionally, converting the Trimetazidine to pharmaceutically acceptable salt thereof.
Preferably, the hydrocarbon is selected from toluene, xylene, benzene, hexane, heptane, halogenated derivatives thereof or mixture thereof; and the alcohol is selected from methanol, ethanol, n-propanol, isopropanol, butanol or mixture thereof. Preferably, the hydrocarbon and alcohol is used in a ratio of 80:20 to 95:5. Preferably, the molar ratio of 2,3,4-trimethoxybenzaldehyde to piperazine is in the range of 1:1.1 to 1:1.6. Preferably, the hydrogenating agent is selected from the group consisting of hydrogen gas, formic acid, hydrazine, sodium borohydride and lithium aluminium hydride. Preferably, the treatment is carried out at a temperature in the range of 60°C to 80°C and pressure in the range of 1 to 5 Kg/cm2 for about 3 to 6 hours.
Another aspect of the present invention provides the process which further

comprises the steps of,
a) filtering the reaction mixture containing Trimetazidine to obtain a filtrate;
b) adding water to the filtrate to obtain a mixture and adjusting the pH of the mixture in the range of 6 to 7 followed by separation of the organic layer and aqueous layer;
c) basifying the aqueous layer followed by extraction of the aqueous layer using an organic solvent;
d) separating and concentrating the organic layer to obtain Trimetazidine as an oily residue; and
e) optionally, converting the oily residue to Trimetazidine salts.
Yet another aspect of the present invention provides the process which further comprises the steps of,
a) filtering the reaction mixture containing Trimetazidine to obtain a filtrate;
b) concentrating the filtrate to obtain an oily residue;
c) treating the oily residue with a mixture of organic solvent and water to obtain a mixture;
d) adjusting pH of the mixture in the range of 6 to 7 followed by separation of the organic layer and aqueous layer;
e) basifying the aqueous layer followed by extraction of the aqueous layer using an organic solvent;
f) separating and concentrating the organic layer to obtain Trimetazidine as an oily residue which is then optionally converted to Trimetazidine salts.
Preferably, the organic solvent is toluene and the adjustment of pH is carried out using hydrochloric acid.
Another aspect of the present invention provides a process for conversion of Trimetazidine to pharmaceutic ally acceptable salts thereof, comprising,
a) treating Trimetazidine with a salt forming agent in presence of a first solvent and/or second solvent to get a solution; and
b) isolating pharmaceutically acceptable salts of Trimetazidine.

Preferably, the first solvent is selected from C1 to C4 alcohol such as methanol, ethanol, n-propanol, isopropanol or mixture thereof; the second solvent is selected from acetone, ethylmethyl ketone, methylisobutyl ketone or mixture thereof; the salt forming agent is hydrochloric acid; and the pharmaceutically acceptable salt is Trimetazidine dihydrochloride.
Preferably, the isolated Trimetazidine dihydrochloride is characterized by X-ray diffraction pattern having peaks at 2-theta values of about 6.82, 11.37, 16.95, 17.85, 18.44, 18.87, 19.27, 19.79, 21.17, 21.53, 21.80, 23.42 and 23.87 degrees.
Brief description of figures:
Fig.l: XRPD of Trimetazidine dihydrochloride obtained according to the present
invention.
Fig. 2: XRPD of Trimetazidine dihydrochloride obtained by following the process as
disclosed in Example 1 of US5142053.
Detailed description of the invention:
The present invention provides a process for preparation of Trimetazidine or pharmaceutic ally acceptable salt thereof.
According to one embodiment of the present invention, the process for preparation of Trimetazidine or pharmaceutically acceptable salt thereof comprises the steps of:
a) treating 2,3,4-trimethoxybenzaldehyde with piperazine in a solvent selected from hydrocarbon, alcohol, ether or mixture thereof in presence of a hydrogenating agent to get a reaction mixture containing Trimetazidine; and
b) optionally, converting obtained Trimetazidine to pharmaceutically acceptable salts thereof.



Scheme II
Hydrocarbon is selected from toluene, xylene, benzene, hexane, heptane, halogenated derivatives thereof or mixture thereof. Alcohol is selected from methanol, ethanol, isopropanol, n-propanol, butanol or mixture thereof. Ether is selected from 1,4-dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert butyl ether or mixture thereof.
According to another embodiment of the present invention, 2,3,4-trimethoxy
benzaldehyde is treated with piperazine in a mixture of hydrocarbon and alcohol in
Presence of a hydrogenating agent to get a reaction mixture containing
Trimetazidine; and optionally, converting obtained Trimetazidine to
Pharmaceutically acceptable salts thereof.
Preferably, hydrocarbon and alcohol are used in the ratio of 80:20 to 95:5, preferably
90:10.
Hydrogenating agent is an agent which will efficiently hydrogenate the unsaturated Compound and is selected from hydrogen gas, formic acid, hydrazine, sodium borohydride or lithium aluminium hydride, preferably hydrogen gas. Hydrogenation using hydrogen gas is carried out in presence of a Catalyst selected from Pd/C, Pt/C, PtO2, Ru/C or Rh/C. the catalyst Pd/C(5-10%) or pt/C(5-10%) is used with loading quantity varying from 1% to 5% with respect to 2,3,4-trimethoxybenzaldehyde. Preferably, 10% Pd/C (50% moist) is used with loading quantity of about 2% with respect to 2,3,4-trimethoxybenzaldehyde.
The hydrogenation reaction is carried out at a temperature in the range of 50°C to

100°C and pressure in the range of 1 to 8 Kg/cm2, preferably at a temperature in the range of 60°C to 80°C, more preferably at temperature of 70°C and pressure of 1 to 5 Kg/cm2 for a period of 3 to 6 hours, preferably 4 hours.
According to a preferred embodiment of the present invention, 2,3,4-trimethoxy benzaldehyde is treated with anhydrous piperazine in a molar ratio of 1:1.1-1:1.6 in a mixture of toluene and methanol in the presence of hydrogen gas and 10 % Pd/C, by initially purging nitrogen followed by hydrogen, preferably 1 Kg/cm2 pressure, to obtain a reaction mixture. The reaction mixture is heated to about 60°C-80°C, preferably at 70°C and hydrogen pressure is increased upto approximately 5 Kg/cm2. The reaction is continued for 3-6 hrs, preferably for 4 hours, to get Trimetazidine, which is not isolated.
Prior art discloses the use of a single solvent such as ether or alcohol for reacting 2,3,4-trimethoxybenzaldehyde and piperazine. It was found by the inventors of the present invention that use of a single solvent does not provide Trimetazidine in high yield and purity .i.e., substantially free of impurities. It has been surprisingly found that use of hydrocarbon and alcohol enables smooth reaction and easy work up. It also provides substantially pure Trimetazidine or pharmaceutically acceptable salts thereof, without the need for further purification.
Prior art reports hydrogenation reaction at high temperature. The inventors of the present invention have found that the reaction does not proceed to completion, when the reaction is carried out at a temperature of less than 70°C and when the reaction is carried out at a temperature above 70°C, impurities get generated. It has been surprisingly found that when the reaction is carried out at a temperature of 70° C, generation of impurities are controlled.
The molar ratio of 2,3,4-trimethoxybenzaldehyde to piperazine, used in the prior art, is in the range of 1:2-1:4. The molar ratio of 2,3,4-trimethoxybenzaldehyde and anhydrous piperazine used in the process of the present invention is in the range of

1:1.1-1:1.6, preferably 1:1.5. Use of this ratio provides Trimetazidine salts in high yield.
Another embodiment of the present invention provides the process for the preparation of Trimetazidine or salts thereof, comprising the steps of:
a) filtering the reaction mixture containing Trimetazidine to obtain a filtrate;
b) adding water to the filtrate to obtain a mixture and adjusting the pH of the mixture in the range of 6 to 7 followed by separation of the organic layer and aqueous layer;
c) basifying the aqueous layer followed by extraction of the aqueous layer using an organic solvent;
d) separating and concentrating the organic layer to obtain Trimetazidine as an oily residue; and
e) optionally, converting the oily residue to Trimetazidine salts.
In a preferred embodiment, the reaction mixture containing Trimetazidine is cooled to room temperature and filtered. The filtrate is treated with water and the pH of the mixture is adjusted in the range of 6 to 7 using hydrochloric acid, preferably conc. hydrochloric acid followed by separation of organic layer. The aqueous layer is basified using suitable base followed by extraction of the aqueous layer using suitable organic solvent. The combined organic layers are dried and concentrated to get Trimetazidine as an oily residue, which is then treated with a salt forming agent to get Trimetazidine salts.
An alternate embodiment of the present invention provides the process for the preparation of Trimetazidine or salts thereof, comprising the steps of:
a) filtering the reaction mixture containing Trimetazidine to obtain a filtrate;
b) concentrating the filtrate to obtain an oily residue;
c) treating the oily residue with a mixture of organic solvent and water to obtain a mixture;
d) adjusting pH of the mixture in the range of 6 to 7 followed by separation of

the organic layer and aqueous layer;
e) basifying the aqueous layer followed by extraction of the aqueous layer using an organic solvent;
f) separating and concentrating the organic layer to obtain Trimetazidine as an oily residue which is then optionally converted to Trinietazidine salts.
In a preferred alternate embodiment, the reaction mixture containing Trimetazidine is filtered. The filtrate containing Trimetazidine is concentrated to obtain an oily residue which is treated with a mixture of organic solvent and water to obtain a mixture. The pH of the mixture is adjusted in the range of 6 to 7 followed by separation of the organic layer. The aqueous layer is basified using suitable base followed by extraction of the aqueous layer using a suitable organic solvent. The combined organic layers are dried and concentrated to get Trimetazidine as an oily residue, which is then treated with a salt forming agent to get Trimetazidine salts.
Prior art teaches adjusting pH to 3-4 during work up. It is observed that adjusting pH in the range of 3 to 4 does not enable the removal of impurities. The advantage of adjusting the pH in the range of 6 to 7 enables the removal of impurities and provides substantially pure Trimetazidine dihydrochloride. Trimetazidine thus obtained is used for the preparation of pharmaceutically acceptable salts thereof, without further purification.
Organic solvent is selected from aromatic hydrocarbon such as toluene, xylene, benzene or mixture thereof.
The base is selected from sodium hydroxide, potassium hydroxide, potassium tertiary butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquor ammonia, sodium hydride, calcium or cesium hydroxide.
Another embodiment of the present invention provides the process of conversion of Trimetazidine to pharmaceutically acceptable salts thereof comprising:

a) treating Trimetazidine with salt forming agents in presence of a first solvent
and/or second solvent to get solution; and
b) isolating pharmaceutic ally acceptable salts of Trimetazidine.
Preferably, the phannaceutically acceptable salt is Trimetazidine dihydrochloride.
In a preferred embodiment, Trimetazidine is in the form of an oily residue. The conversion of Trimetazidine to Trimetazidine dihydrochloride is carried out by treating Trimetazidine with first solvent preferably alcohol and suitable salt forming agent at a temperature of 50°C to 60°C to obtain a reaction mixture. The reaction mixture is cooled to room temperature, preferably at 25°C to 35°C to precipitate Trimetazidine dihydrochloride which is filtered, washed and dried at 60° to 70°C for about 6 hours to get substantially pure Trimetazidine dihydrochloride.
Optionally second solvent, preferably ketone is used in combination with first solvent.
The first solvent used is selected from C1 to C4 alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol or mixture thereof, preferably methanol. The second solvent is a ketone such as acetone, ethylmethyl ketone, methylisobutyl ketone or mixture thereof, preferably acetone.
The salt forming agent is hydrochloric acid. Alternatively, thionyl chloride or ammonium chloride can be used.
Trimetazidine dihydrochloride obtained according to the present invention has purity of more than about 99.8%, having all known impurities below 0.15% and all unknown impurities below 0.1%, which is as per the ICH guidelines.
The starting materials, 2,3,4-trirnethoxybenzaldehyde and piperazine are commercial products. 2,3,4-trimethoxybenzaldehyde can be prepared by any method known in the art. In a preferred embodiment of the present invention, 2,3,4-trimethoxy benzaldehyde can be prepared by Vilsmeier Haack reaction. The process comprises treating phosphorusoxychloride with a substituted amide to obtain a complex. 1,2,3-

trimethoxybenzene is treated with the complex in the presence of a suitable solvent to get a reaction mixture. The obtained reaction mixture is maintained for 3-5 hours, preferably for 4 hours at a temperature of about 80°C-110°C, preferably at 90°C-100°C. The reaction mixture is quenched in ice-cooled solution and basified till the pH of 9-10 is achieved. The obtained reaction mass is extracted with a halogenated hydrocarbon followed by evaporation of the halogenated hydrocarbon extract to get an oil which is subjected to short path distillation to get 2,3,4-trimethoxy benzaldehyde.
Suitable solvent used is N,N-dimethylformamide, N,N-dirnethylacetamide, N-methylacetamide, N,N-dimethylpropionamide, preferably N,N-dimethylformamide. The base used is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. The halogenated hydrocarbon used is selected from chloroform, carbon tetrachloride, methylene dichloride (MDC), ethylene chloride, 1,1,1 -trichloroethane, 1,1,2-ethylene trichloride or mixture thereof.
1,2,3-trimethoxybenzene, the starting material for the preparation of 2,3,4-trimethoxybenzaldehyde can be prepared by any process known in the art. It can be prepared by treating pyrogallol with dimethyl sulphate in the presence of potassium carbonate and a suitable solvent at a temperature of 50°C-65°C, preferably 55°C-60°C for 3-5 hrs, preferably for 4 hours.
The solvent used is selected from ester, ketone or mixture thereof. Ester is selected from methyl acetate, ethyl acetate or butyl acetate; ketone is selected from acetone, methylethyl ketone, methylisobutyl ketone or mixture thereof.
The process for preparation of Trimetazidine dihydrochloride as described herein can be used to prepare different salts of Trimetazidine.
The present invention provides a consistent process for preparation of Trimetazidine and its dihydrochloride salt wherein Trimetazidine dihydrochloride is prepared

without isolation and purification of Trimetazidine base.
Trimetazidine dihydrochloride obtained according to the present invention is crystalline in nature and is characterized by X-ray diffraction pattern as shown in Fig. 1. Trimetazidine dihydrochloride is characterized by X-ray diffraction pattern having peaks expressed as 20 values of about 6.82, 11.37, 16.95, 17.85, 18.44, 18.87, 19.27, 19.79, 21.17, 21.53, 21.80, 23.42 and 23.87. It is further characterized by peaks expressed as 20 values of about 16.24, 20.38, 22.23, 22.95, 24.06, 26.01, 26.27, 27.09, 27.33, 27.95, 28.67, 29.14 and 29.68 degrees.
Trimetazidine dihydrochloride obtained by following the process as disclosed in Example 1 of US5142053 is characterized by X-ray diffraction pattern as shown in Fig. 2.
According to one embodiment of the present invention, Trimetazidine dihydrochloride obtained is passed through 30 mesh sieve to obtain particle size distribution, such that 90% of particles have a particle size less than about 100 microns, preferably less than about 50 microns, more preferably less than about 25 microns. Preferably, 90% of particles have particle size less than about 15 µ, 50% of particles have particle size less than about 10µ and 10% of particles have particle size less than about 5µ.
Trimetazidine or pharmaceutically acceptable salts thereof or polymorphic forms thereof obtained according to the process of the present invention may be micronized by conventional micronization techniques for improving the flow characteristics, bioavailability and uniformity of dosage forms.
The advantages of the present invention are:
• It is a simple, readily scalable and robust process for preparation of Trimetazidine dihydrochloride.
• It does not require purification of Trimetazidine or Trimetazidine

dihydrochloride thus being cost effective and commercially viable.
• Same solvents are used for the reaction and further work up which makes the process cost effective and commercially viable.
• It provides substantially pure Trimetazidine dihydrochloride which meets the ICH requirements.
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term "substantially pure" means Trimetazidine or salts thereof comprising less than 5%, preferably less than 2.5%, more preferably less than 1% of undesired impurities.
The term "room temperature" means the temperature in range of 20°C-40°C preferably 25°C-30°C.
The term "micronization" means a process or method by which the size of particles are reduced. The term " micron" refers to 'micrometer' which is 1x10-6 meter.
The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for human pharmaceutical use.
X-ray powder diffraction pattern (XRPD) has been obtained on PANalytical X'pert Pro diffractometer equipped with accelerator detector using Copper Ka (X = 1.5406 A0) radiation with scanning range between 2-theta 2-50° at a scanning speed of 2°/min.
The present invention is further illustrated by reference to the following examples which does not limit the scope of the invention in any way.

Examples
Example 1
Preparation of Trimetazidine dihydrochloride
6 Kg of 2,3,4-trimethoxybenzaldehyde, 3.9 Kg of anhydrous piperazine, 3 L of methanol, 27 L of toluene and 0.12 Kg of 10% Pd/C (50% moist) were charged in a reactor and nitrogen was purged into the reactor followed by hydrogen (1 Kg/cm2 pressure). The reaction mass was heated to 70°C, hydrogen pressure was increased to 5 Kg/cm2 and the reaction was continued for 4 hours. After the completion of reaction, the reaction mass was cooled to 25°C to 35°C and filtered. 25 L of water was added to the obtained filtrate and pH of the mixture was adjusted between 6 to 7 by the addition of concentrated hydrochloric acid. The separated aqueous layer was basified with 3.5 Kg of sodium hydroxide. The basic aqueous layer was treated with 18 L of toluene. The toluene layer was separated and aqueous layer was washed with toluene (2x9 L). The combined toluene extracts were dried on anhydrous sodium sulphate and evaporated to dryness to get an oily residue.The obtained oily residue was treated with 16 L of methanol, 40 L of acetone and 5.9 L of concentrated hydrochloric acid at 50°C to 60°C. The reaction mixture was cooled to 25°C to 35°C. The precipitated Trimetazidine dihydrochloride was filtered, washed with 16L acetone and dried at 60°C to 70°C for 6 hrs. Yield: 91%, Purity: 99.98%
Example 2
Preparation of Trimetazidine dihydrochloride
100 g of 2,3,4-trimethoxybenzaldehyde, 65 g of anhydrous piperazine, 50 ml of methanol, 450 ml of toluene and 2 g of 10% Pd/C (50% moist) were charged in a reactor and nitrogen was purged into the reactor followed by hydrogen (1 Kg/cm2 pressure). The reaction mixture was heated to 70°C and hydrogen pressure was increased to 5 Kg/cm2. The reaction was continued for 4 hours. After the completion of reaction, the reaction mass was cooled to 25°C to 35°C and filtered. 400 ml of water was added to the obtained filtrate and pH of the mixture was adjusted between

6 to 7 by the addition of concentrated hydrochloric acid. The separated toluene layer was discarded and the aqueous layer was basified with 58g of sodium hydroxide. The basic aqueous layer was treated with 300ml of toluene. The toluene layer was separated and aqueous layer was washed with toluene (2 x 150ml). The combined toluene extracts were dried on anhydrous sodium sulphate and evaporated to dryness to get an oily residue. The obtained oily residue was treated with 260 ml of methanol, 650 ml of acetone and 95 ml of concentrated hydrochloric acid at 50°C to 60°C. The reaction mixture was cooled to 25°C to 35°C. The precipitated Trimetazidine dihydrochloride was filtered, washed with 260 ml acetone and dried at 60° to 70°C for 6 hrs. Yield : 91%, Purity : 99.98%, m.p.: 228-234°C
Example 3
Preparation of Trimetazidine dihydrochloride
50 g of 2,3,4-trimethoxybenzaldehyde, 44 g of anhydrous piperazine, 250 ml of 1,4-dioxane and 2.5 g of 10% Pd/C (50% moist) were introduced into a reactor and nitrogen was purged into the reactor followed by hydrogen (1 Kg/cm2 pressure). The reaction mixture was heated to 70°C and hydrogen pressure was increased to 5 Kg/cm2. The reaction was continued for 4 hours. After the completion of reaction, the reaction mass was cooled to 25°C to 35°C and filtered. The clear filtrate was concentrated to remove 1,4-dioxane to get oily residue. The obtained residue was treated with 400 ml of toluene and 400ml of water and pH of the reaction mixture was adjusted between 6 to 7 by addition of concentrated hydrochloric acid. The toluene layer was separated and the aqueous layer was basified with 28 g of sodium hydroxide. The aqueous layer was further treated with 150ml toluene. The toluene layer was separated and the aqueous layer was washed with toluene (2 x 75 ml). The combined toluene extracts were dried on anhydrous sodium sulphate and evaporated to dryness to get an oily residue. The obtained oily residue was treated with 300 ml of isopropanol and 100 ml of concentrated hydrochloric acid at 50°C to 60°C. The reaction mixture was cooled to 25°C to 35°C. The precipitated Trimetazidine

dihydrochloride was filtered, washed with 260ml acetone and dried at 60° to 70°C
for 6 hrs.
Yield : 78%, Purity : 99.98%
Example 4 : Preparation of Trimetazidine dihydrochloride
100 g of 2,3,4-trimethoxybenzaldehyde, 65 g of anhydrous piperazine, 250 ml of methanol and 2 g of 10% Pd/C (50% moist) were charged in a reactor and nitrogen was purged into the reactor followed by hydrogen (1 Kg/cm2 pressure). The reaction mixture was heated to 70°C and hydrogen pressure was increased to 5 Kg/cm2 . The reaction was continued for 4 hours. After the completion of reaction, the reaction mass was cooled to 25°C to 35°C and filtered. The clear filtrate was concentrated to remove methanol completely to get oily residue. The obtained oily residue was treated with 400 ml of tofuene and 400 ml of water and pH of the mixture was adjusted between 6 to 7 by the addition of concentrated hydrochloric acid. The toluene layer was separated and the aqueous layer was basified with 58g of sodium hydroxide. The basic aqueous layer was treated with 300ml of toluene. The toluene layer was separated and aqueous layer was extracted with toluene (2 x 150ml). The combined toluene extracts were dried on anhydrous sodium sulphate and evaporated to dryness to get an oily residue.The obtained oily residue was treated with 260 ml of methanol, 650 ml of acetone and 95 ml of concentrated hydrochloric acid at 50°C to 60°C. The reaction mixture was cooled to 25° to 35°C. The precipitated Trimetazidine dihydrochloride was filtered, washed with 260 ml acetone and dried at 60° to 70° C for 6 hrs. Yield : 84%, Purity : 99.98%
Example 5
Preparation of 2,3,4-trimethoxybenzaldehyde
Stage 1: 1,2,3-Trimethoxybenzene
A mixture of 20 Kg pyrogallol and 88 Kg potassium carbonate in 200 L acetone was treated with 80Kg dimethyl sulphate maintaining temperature between 25°C-35°C. The reaction mixture was heated to 55°C-60°C and maintained for 4 hours. The

reaction mixture was filtered to remove insolubles. The clear filtrate was collected and concentrated to remove acetone completely. The obtained brown oil was treated with 60 L of ethyl acetate and 100L of water. The separated organic layer was collected and concentrated to get residue of 1,2,3-trimethoxy benzene. Yield : 68%, Purity : more than 96 %
Stage II: 2,3,4-trimethoxy benzaldehyde
To pre-cooled (0°C-10°C) dimethyl formamide (35Kg), 45L of phosphorus oxychloride was charged gradually. The complex was warmed gradually to 25°C-35° C. 14 Kg of 1,2,3-trimethoxybenzene dissolved in 25L dimethyl formamide was added to the reaction mixture and maintained for 4h at 90°C-100°C. The reaction mixture was quenched in 50L ice cooled solution and basified with 10% sodium hydroxide solution to attain pH between 9-10. The reaction mass was extracted with methylene dichloride (3 x 50L). The combined methylene dichloride extracts were evaporated to get an oil which was distilled over short path to get 2,3,4-trimethoxy benzaldehyde. Yield : 88%, Purity : more than 99 %

We claim:
1. A process for preparation of Trimetazidine or pharmaceutically acceptable
salts thereof comprising,
a) treating 2,3,4-trimethoxybenzaldehyde with piperazine in a mixture of hydrocarbon and alcohol in presence of a hydrogenating agent to get a reaction mixture containing Trimetazidine; and
b) optionally, converting said Trimetazidine to pharmaceutically acceptable salts thereof

2. The process as claimed in claim 1, wherein said hydrocarbon is selected from toluene, xylene, benzene, hexane, heptane, halogenated derivatives thereof or mixture thereof; and wherein said alcohol is selected from methanol, ethanol, n-propanol, isopropanol, butanol or mixture thereof.
3. The process as claimed in claim 2, wherein said hydrocarbon and said alcohol is used in a ratio of 80:20 to 95:5.
4. The process as claimed in claim 1, wherein said 2,3,4-trimethoxybenzaldehyde and said piperazine are used in the molar ratio of 1:1.1 to 1:1.6.
5. The process as claimed in claim 1, wherein said hydrogenating agent is selected from the group consisting of hydrogen gas, formic acid, hydrazine, sodium borohydride and lithium aluminium hydride.
6. The process as claimed in claim 1, wherein said hydrogenating agent is hydrogen gas and said treatment in step a) is carried out at a temperature in the range of 60°C to 80°C and pressure in the range of 1 to 5 Kg/cm2 for about 3 to 6 hours.

7. The process as claimed in claim 6, wherein said hydrogenating agent is hydrogen gas and said treatment in step a) is carried out at a temperature of 70°C and pressure of 5 Kg/cm2 for 4 hours.
8. The process as claimed in claim 1, wherein said process further comprises the steps of:

a) filtering said reaction mixture containing Trimetazidine to obtain a filtrate;
b) adding water to said filtrate to obtain a mixture and adjusting the pH of the mixture in the range of 6 to 7 followed by separation of the organic layer and aqueous layer;
c) basifying said aqueous layer followed by extraction of the aqueous layer using an organic solvent;
d) separating and concentrating the organic layer to obtain Trimetazidine as an oily residue; and
e) optionally, converting said oily residue to Trimetazidine salts.
9. The process as claimed in claim 1, wherein said process further comprises
the steps of:
a) filtering said reaction mixture containing Trimetazidine to obtain a filtrate;
b) concentrating said filtrate to obtain an oily residue;
c) treating said oily residue with a mixture of organic solvent and water to obtain a mixture;
d) adjusting pH of said mixture in the range of 6 to 7 followed by separation of the organic layer and aqueous layer;
e) basifying said aqueous layer followed by extraction of the aqueous layer using an organic solvent;
f) separating and concentrating the organic layer to obtain Trimetazidine as an oily residue which is then optionally converted to Trimetazidine salts.

10. The process as claimed in claim 8 or 9, wherein said organic solvent is toluene; and wherein said adjustment of pH is carried out using hydrochloric acid.
11. The process as claimed in claim 1, wherein said process of conversion of Trimetazidine to pharmaceutically acceptable salts thereof as in step (b) comprises,

a) treating said Trimetazidine with a salt forming agent in presence of a first solvent and/or second solvent to get a solution; and
b) isolating pharmaceutically acceptable salts of Trimetazidine.

12. The process as claimed in claim 11, wherein said first solvent is selected from methanol, ethanol, n-propanol, isopropanol or mixture thereof; wherein said second solvent is selected from acetone, ethylmethyl ketone, methylisobutyl ketone or mixture thereof; wherein said salt forming agent is hydrochloric acid; and wherein said pharmaceutically acceptable salt is Trimetazidine dihydrochloride.
13. The process as claimed in claim 12, wherein said isolated Trimetazidine dihydrochloride is characterized by X-ray diffraction pattern having peaks at 2-theta values of about 6.82, 11.37, 16.95, 17.85, 18.44, 18.87, 19.27, 19.79, 21.17, 21.53, 21.80, 23.42 and 23.87 degrees.