FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10 and rulel3)
1. TITLE OF THE INVENTION:PROCESS FOR RANOLAZINE PIPERAZINE INTERMEDIATE
2. APPLICANT (S)(a) NAME: WOCKHARDT LTD.(b) NATIONALITY: INDIAN(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTIONThe present invention relates to a process for 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine, as a key ranolazine intermediate.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention relates to a process for 1-[(2,6-dimethylphenyl)amino carbonylmethyl]piperazine, as a key ranolazine intermediate.
Ranolazine of Formula I, is chemically 1-piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-,(±) and it is indicated for the treatment of chronic angina.

Formula I
U.S. Patent No. 4,567,264 discloses racemic (±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl].The '264 patent further discloses the process for ranolazine intermediate, 1-[(2,6-dimethylphenyl)aminocarbonyl methyl]piperazine wherein the condensation is carried out in ethanol under reflux.
European application EP483932 A1 discloses the use of 1-(2-methoxyphenoxy)-3-aminopropan-2-ol as intermediate for ranolazine preparation.
PCT application WO2006008753 disclosed polymorphic Form A of Ranolazine, and process for the same.
The process for ranolazine intermediate, 1-[(2,6-dimethylphenyl)aminocarbonyl methyl]piperazine, when carried out at reflux temperature involves higher levels of dimmer impurity of formula II,
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The present inventors have surprisingly found that the process for ranolazine intermediate, 1 -[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine when carried out at a temperature below 65 °C, leads to a reduced levels of dimer impurity of formula II.
In one aspect of the present invention there is provided a process for ranolazine intermediate, 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine compound of formula III. The process includes step of,

a) reacting piperazine with [(2,6-dimethylphenyl)-aminocarbonylmethyl] chloride in presence of a organic solvent at a temperature below 65 °C;
b) isolating 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine from reaction mass thereof.
Preferably, the process of ranolazine intermediate 1-[(2,6-dimethylphenyl)amino carbonylmethyl]piperazine is carried out at a temperature below 65 °C. More preferably, the process of ranolazine intermediate is carried out at a temperature below 40 °C. Most preferably, the process of ranolazine intermediate is carried out at a temperature below 20-30 °C.
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In another aspect the organic solvent of step a) is selected form the group comprising one or more of t-butanol, n-butanol, isopropanol, n-propanol, ethanol, methanol, 1,4-dioxane, tetrahydrofuran, acetone, acetonitrile, Methyl isobutyl ketone (MIBK), Methyl ethyl ketone and the like.
The 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine, so obtained is coupled with epoxy propane intermediate under reflux to obtain ranolazine or salts thereof.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Examplel: Process for 1-[(2,6-dimethylphenyl)aminocarbonylmethvl]piperazine.
To a stirred mixture of Piperazine (174g) in isopropanol at 25-30 °C was added [(2,6-dimethylphenyl)-aminocarbonylmethyl] chloride (100 g) in lots. The resultant mass was further stirred for another 2 hrs, filtered and dried to obtain the title compound.
Example2: Process for 1-f(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine.
To a stirred mixture of Piperazine (174g) in isopropanol and Methyl ethyl ketone solvent system at 25-30 °C was added [(2,6-dimethylphenyl)-aminocarbonylmethyl] chloride (100 g) in lots. The resultant mass was further stirred for another 2 hrs, filtered and dried to obtain the title compound.
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WE CLAIM:
1. A process for purification of ranolazine intermediate, 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine compound of formula III. The process comprising,

Formula III
a) reacting piperazine with [(2,6-dimethylphenyl)-aminocarbonylmethyl] chloride in presence of a organic solvent at a temperature below 65 °C;
b) isolating 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine from reaction mass thereof.

2. The process of claim 1, wherein the organic solvent comprises one or more of t-butanol, n-butanol, isopropanol, n-propanol, ethanol, methanol, 1,4-dioxane, tetrahydrofuran, acetone, acetonitrile, Methyl isobutyl ketone (MIBK), Methyl ethyl ketone and the like.
3. The process of claim 1, wherein the solvent is isopropanol.

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Abstract
The present invention relates to improved process for 1-[(2,6-dimethylphenyl) aminocarbonylmethyl]piperazine, as a ranolazine intermediate.