FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
IMPROVED PROCESS FOR PREPARATION OF RANOLAZINE
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 present invention relates to an improved process for the preparation of 1-(2-methoxyphenoxy)-2,3-epoxypropane, a key intermediate for the preparation of ranolazine.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention relates to an improved process for the preparation of 1-(2-methoxyphenoxy)-2,3-epoxypropane, a key intermediate for the preparation of ranolazine.
Ranolazine of Formula I, is chemically known as (±)1-piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl] and is indicated for the treatment of chronic angina.

Formula

U.S. Patent No. 4,567,264 discloses ranolazine and process for preparation of its intermediate, 1-(2-methoxyphenoxy)-2,3-epoxypropane (Formula II) wherein sodium hydroxide was used as a base in dioxane/water solvent system. This process results in about 50:50 ratio of product (epoxide, formula II) and hydroxyl dimer impurity (Formula III). The hydroxyl dimmer impurity of formula ill which is produced in a very high concentration results in decreased yield of the intermediate formed.
0H III
OMe
.o. s—o II ^ .o. A .o.

European application EP483932 A1 discloses the use of 1 -(2-methoxyphenoxy)-3-aminopropan-2-ol as an intermediate in ranolazine preparation.

PCT application WO2006008753 disclosed polymorphic Form A of ranolazine, and its process.
The inventors have now developed an improved process for the preparation of 1-(2-methoxyphenoxy)-2,3-epoxypropane (epoxide intermediate), an useful intermediate for the preparation of ranolazine. The inventors found that use of phase transfer catalyst for the preparation of epoxide intermediate i.e. 1-(2-methoxyphenoxy)-2,3-epoxypropane in biphasic solvent at a controlled temperature provides high yield and purity of intermediate. The controlled reaction condition obstruct the formation of dimer impurity of formula III which results high yield and purity of intermediate when measured by HPLC.
In one of the aspect of, present invention there is provided a process for the preparation of ranolazine epoxide intermediate of formula II,
^^^OMe
the process includes steps of
a) reacting 2-methoxyphenol with epichlorhydrin in a biphasic solvent in presence of a phase transfer catalyst under controlled temperature,
b) isolating compound of formula II from the reaction mixture thereof.
The 2-methoxyphenol and epichlorhydrin are condensed in presence of phase transfer catalysts in biphasic solvent in which one solvent is essentially water and other is an organic solvent. The reaction is carried out under controlled temperature of 50 °C or less. The product is isolated by mean of distillation under reduced pressure. The product obtained in the present process is of higher purity i.e. 97 % or more with 95:5 ratio of product (epoxide intermediate, formula II) and

hydroxyl dimer impurity (Formula III) respectively, when measured by HPLC. The compound of formula II is used for the synthesis of ranolazine by the method known in the art as disclosed in U.S. Patent No. 4,567,264.
The phase transfer catalyst may include one or more of quaternary ammonium
salts which includes tetra-n-butylammonium bromide , methyltrioctylammonium
chloride, tetrabutylammonium bromide, tetrapropylammonium bromide,
tributylbenzylammonium chloride, tetraethylammonium bromide,
tetraoctylammonium bromide, tetrabutylammonium hydrogen sulphate, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium acetate, ethyltriphenylphosphonium bromide and tetrabutylammonium iodide.
The organic solvents may include one or more solvents from the group of polar aprotic solvents including tetrahydrofuran (THF), dioxane, dimethylsulfoxide, dimethylacetamide and dimethylformamide. The organic solvent may also include one or more solvents from the group of halogenated solvents including chloroform, carbontetrachloride and dichloromethane.
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 1: Preparation of 1-(2-methoxvphenoxv)-2,3-epoxypropane
To a stirred solution of 2-methoxyphenol (100 g) in THF (500 ml_), aqueous sodium hydroxide solution (79 g/147 ml_ of water) was added slowly at below 50 °C in 30 minutes. Benzyltriethylammonium chloride (80 g) was then added to the above solution. Solution was stirred for 15 minutes. Epichlorhydrin (461 g) was added in 2 hours and the reaction mixture was further stirred for another 2 hour.


The reaction mixture was quenched with water, extracted with ethyl acetate (500 mL X 2), and concentrated to get an oily mass of crude epoxide. The crude oily mass was subjected to distillation under reduced pressure and pure fraction was collected at 120-38° C vapor temperature at 2-4 mm Hg pressure. Yield: 97 g HPLC Purity : 97 %


WE CLAIM:
1. A process for the preparation of 1-(2-methoxyphenoxy)-2,3-
epoxypropane of formula II, an useful intermediate for the preparation of ranolazine

OMe
the process comprises of,
a) reacting 2-methoxyphenol with epichlorhydrin in a biphasic solvent system in presence of a phase transfer catalyst under controlled temperature,
b) isolating compound of formula II from the reaction mixture thereof.

2. The process of claim I, wherein the biphasic solvent system include mixture of an organic solvent and water.
3. The process as per claim 2, wherein organic solvent includes one or more solvents from the group of polar aprotic solvents including tetrahydrofuran (THF), dioxane, dimethylsulfoxide, dimethylacetamide and dimethylformamide.
4. The process as per claim I, wherein phase transfer catalyst belongs to the class of quarternary ammonium salts.
5. The quaternary ammonium salts of claim 4, are from the group of tetra-n-butylammonium bromide, methyltrioctylammonium chloride, tetrabutylammonium bromide, tetrapropylammonium bromide, tributylbenzylammonium chloride, tetraethylammonium bromide, tetraoctylammonium bromide, tetrabutylammonium hydrogen


sulphate , benzyltrimethylammonium chloride, benzylthethylammonium
chloride, tetrabutylammonium acetate, ethyltriphenylphosphonium
bromide and tetrabutylammonium iodide.
6. The process of claim 5, wherein phase transfer catalyst is benzyltriethylammonium chloride.
7. The process of claim 1 wherein controlled temperature is 50 °C or less.
8. The process as per claim 7, wherein the temperature is below 30 °C.
9. The ranolazine intermediate 1-(2-methoxyphenoxy)-2,3-epoxypropane, of claim 1, has purity of 97 % or more by HPLC.
9. The ranolazine intermediate 1-(2-methoxyphenoxy)-2,3-epoxypropane of formula II, having less than 5 % of dimer impurity of formula III.

Abstract
The present invention relates to a process for the preparation of 1-(2-methoxyphenoxy)2,3-epoxypropane as a ranolazine intermediate in presence of phase transfer catalyst and in biphasic solvent at controlled temperature.