FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
AN IMPROVED PROCESS FOR PURIFICATION OF RANOLAZINE PIPERAZINE INTERMEDIATE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The invention relates to an improved process for purification of 1-[(2,6-
dimethyl phenyl)aminocarbonylmethyl]piperazine, an useful ranolazine intermediate.
The following specification particularly describes the invention and the manner
in which it is to be performed.

4. DESCRIPTION
The invention relates to an improved process for purification of 1-[(2,6-dimethyl phenyl)aminocarbonylmethyl]piperazine, an useful ranolazine intermediate.
Ranolazine of Formula I, chemically known as 1-piperazineacetamide, N-(2,6-dimethyl phenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-,(±) and 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 purification of ranolazine intermediate, 1-[(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine using hexane.
European application EP483932 A1 discloses the use of 1-(2-methoxyphenoxy)-3-aminopropan-2-ol as an intermediate for ranolazine preparation.
PCT publication No. WO2006008753 disclosed polymorphic Form A of Ranolazine, and process for the same.
The process for purification of ranolazine intermediate, 1-[(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine, using hexane leads to a product having static charge. More over the product isolated from hexane is contaminated with the dimer impurity of formula II.

The inventors have developed the process for purification of 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine i.e. piperazine intermediate useful for the preparation of ranolazine. The process of invention involves treating crude piperazine intermediate with the organic acid to get acid addition salt of piperazine intermediate. The above salt after hydrolysis gives piperazine intermediate of purity more than 99.5 % with the dimmer impurity level reduced to 0.3 % or less, when measured by HPLC.
In one aspect of the present invention there is provided a process for purification of piperazine intermediate for ranolazine of formula III.

Formula
The process includes the step of,
a) adding piperazine intermediate to an organic acid in solvent to get acid-addition salt of fomula III,
b) treating the product of step a) in the mixture of water and halogenated solvent in presence of base,
c) isolating pure piperazine intermediate of ranolazine from reaction mixture and thereof.

The process involves adding piperazine intermediate of purity 97% or less and dimer impurity more then 0.5% with an organic acid to make acid addition salt. The acid addition salt is hydrolysed in a mixture of halogenated solvent and water in presence of base, such as alkaline metal or alkaline earth metal hydroxide carbonate and bicarbonate at alkaline pH 7.2 or more to give pure piperazine intermediate. Then halogenated solvent is removed and product is isolated by addition of methyl tert-butyl ether or other suitable anti-solvents to precipitate piperazine intermediate from the reaction mass. The precipitated mass is filtered and dried suitably to get piperazine intermediate having purity greater than 99.5 % when measured by HPLC. The level of dimer impurity is obtained in the range of 0.3 % or less.
The bases are from hydroxide, carbonate, and bicarbonate salt of alkaline metal or alkaline earth metal like sodium or potassium.
The organic acid used for making acid addition salts may includes tartaric acid, citric acid, oxalic acid and maleic acid.
The term organic solvents are defined as polar protic solvent, aromatic hydrocarbon, ether which includes methanol, ethanol, ethylene glycol, isopropyl alcohol, xylene, toluene, chlorobenzene, nitrobenzene.
The halogenated solvent includes methylene chloride and chloroform.
The term Isolation involves general techniques like filtration, decantation, centrifugation or evaporation of a solution. Isolation may also include use of anti-solvent like diethyl ether, methyl tert-butyl ether, ethyl tert-butyl ether or diisopropyl ether or mixtures thereof. The removal of solvent may include removal by concentration of solvent which includes distillation, distillation under reduced pressure or evaporation of the solvent.

The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Dryer.
The 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine so obtained is used for making ranolazine by the method known in the art for example U.S. Patent No. 4,567,264.
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.
Example : Purification of piperazine intermediate
To the crude piperazine intermediate (110 g) in methanol (1.1 L) was added L(+)-tartaric acid (137 g) at 40 to 50 °C. The reaction mixture was stirred for 30 minutes at the same temperature and then cooled the contents slowly to 20-30 °C. The reaction mixture was further stirred for 2 hour at same temperature. The precipitated product was filtered, washed with methanol (250 ml) and dried at 45-50 °C to get (241 g) of piperazine intermediate tartrate salt.
The piperazine tartrate salt (240 g) was dissolved in methylene chloride (1.2 L) and water (240 ml). The pH of reaction mixture is adjusted to 7.5 to 10 with 20 % aqueous solution of sodium carbonate. After completion of reaction, the methylene chloride layer was separated and concentrated. The residue is treated with methyl t-butyl ether (MTBE) (200 ml) and reaction mass is stirred for 1 hour. The product was filtered and dried. Yield: 92.5 g (75%) HPLC purity: >99.5 %, Dimer impurity: (0.1 %).


WE CLAIM:
1. A process for purification of ranolazine intermediate, of formula III
Wherein the process comprises of,
a) adding piperazine intermediate to an organic acid in solvent to get acid-addition salt of fomula III,
b) treating the product of step a) in the mixture of water and halogenated solvent in presence of base,
c) isolating pure piperazine intermediate of formula III from reaction mixture thereof.

2. The process of claim 1, wherein the organic acid include tartaric acid, citric acid, oxalic acid and maleic acid.
3. The process of claim 1, wherein solvent selected from the group of methanol, ethanol, isopropyl alcohol, xylene, toluene and mixtures thereof.
4. The process of claim 3, wherein the solvent is methanol.
5. The process of claim 1, wherein the base is hydroxide, carbonate, and bicarbonate salt of alkaline metal or alkaline earth metal like sodium or potassium.

6. The process of claim 1, wherein halogenated solvents including methylene chloride or chloroform.
7. The process in claim 1, wherein isolation is performed by adding antisolvent such as diethyl ether, methyl tert-butyl ether, ethyl tert-butyl ether or diisopropyl ether or mixtures thereof.
8. The ranolazine intermediate of claim 1, having purity 99.5 % by HPLC.
9. The ranolazine intermediate of claim 8, having not more than 0.1 % of dimer
impurity of formula II.

Abstract
The invention relates to an improved process for purification of 1-[(2,6-dimethyl phenyl)aminocarbonylmethyl]piperazine, an useful ranolazine intermediate.