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:
PROCESS FOR PREPARATION OF RANOLAZINE FREE BASE.
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 present invention relates to a process for preparation of ranolazine free base.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention relates to a process for preparation of ranolazine free base. The invention further provides Ranolazine free base having purity 98 % or more.
Ranolazine of Formula I, chemically known as 1-piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-, (±) is indicated for the treatment of chronic angina.

U.S. Patent No. 4,567,264 discloses racemic (±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl.
European application EP483932 A1 discloses the process of preparation of ranolazine wherein free ranolazine base obtained during the process was purified using column chromatography.
PCT application WO2006008753 disclosed polymorphic Form A of Ranolazine, and process for the same. Application '753 further discloses the process of preparation of ranolazine free base from its dihydrochloride salt.
The inventors have surprisingly found a process to isolate ranolazine free base as a solid, when developing the process for the preparation of ranolazine. After the coupling of 1-(2-methoxyphenoxy)-2,3-epoxypropane with 4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine in an organic solvent the

ranolazine base is crystallized out from the reaction mixture. The isolated ranolazine base is crystalline in nature and having purity 98 % or more when measured buy HPLC. Ranolazine free base reacted with acids to obtained corresponding salt of ranolazine. The process of the present invention is economical, simple and cost effective.
In one aspect of the present invention there is provided a process for preparation
of ranolazine free base,
wherein the process includes steps of,
a) coupling 1-(2-methoxyphenoxy)-2,3-epoxypropane compound of Formula
II, with 4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine compound
of Formula III in an organic solvent;

Formula II Formula III
b) isolating ranolazine free base from the reaction mixture thereof,
c) converting ranolazine free base into its salts.
The process of the present invention involves coupling of 1-(2-methoxyphenoxy)-2,3-epoxypropane with 4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine in an organic solvent. The coupling reaction is carried out at temperature 60 °C or less. After completion of the reaction the ranolazine free base is precipitate out which is isolated and dried. The ranolazine base shows purity more than 98% when measured by HPLC.

The examples of organic solvent include polar solvents comprising n-butanol, isopropanol (IPA), n-propanol, ethanol, methanol, tetrahydrofuran, dioxane, dimethylformamide and mixtures thereof.
The term Isolation involves general techniques like filtration, decantation, centrifugation or evaporation of a solution. 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 ranolazine free base thus obtained by the process of present invention can be converted to its acid addition salts by the process known to the skilled artisan for example as disclosed in U.S. Patent No. 4,567,264.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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 : Process for the Ranolazine base
The 4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine (25 g) was suspended in isopropyl alcohol (175 ml) at room temperature followed by 1-(2-methoxyphenoxy)-2,3-epoxypropane (22.9 g). The reaction mass was heated to 45-50 °C and further stirred at same temperature for 6 hour. After completion of the reaction, the crystallized product was filtered and dried to get Ranolazine base.
Yield: 31 g HPLC Purity: 98.6%

WE CLAIM:
1. A process for preparation of ranolazine free base, Wherein the process comprises of,
a) coupling 1-(2-methoxyphenoxy)-2,3-epoxypropane compound of Formula II, with 4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine compound
of Formula III in an organic solvent,

Formula II Formula III
b) isolating ranolazine free base from the reaction mixture thereof,
c) converting ranolazine free base into its salts.

2. The process of claim 1, wherein the organic solvent is selected from the group of polar solvents or hydrocarbons or mixtures thereof.
3. The process of claim 2, wherein polar solvent is alcohol.
4. The process of claim 3, wherein alcohol is selected from group of methanol, ethanol, propanol and isopropanol.
5. The process of claim 1, wherein the coupling is carried out at a temperature 60 °C or less.
6. The process as per claim 5, wherein the controlled temperature is 40-60 °C.

7. A ranolazine free base having purity 98 % or more when measured by HPLC.

Abstract
The present invention relates to a process for preparation of ranolazine free base. The invention further provides Ranolazine free base having purity 98 % or more.