1. TITLE OF THE INVENTION:
A PROCESS FOR PREPARATION OF 1-(2-METHOXYPHENOXY)-2,3-EPOXYPROPANE A RANOLAZINE INTERMEDIATE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: D-4, M.I.D.C. Area, Chikalthana, Aurangabad - 431210
(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 a 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 a% (±)l-piperazineacetamide, N-
(2,6-dimethylphenyl)-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 ranolazine anj process for preparation of its
intermediate, 1-(2-methoxyphenoxy)-2,3-epoxyprot>ane (Formula II).
Pchelka et al. reported synthesis of 3-aryloxy-1 ,^-epoxypropanes using phase
transfer catalyst and microwave irradiations in Tetrahedron (2006), 62(47),
10968-10979.

Formula II European application EP483932 A1 discloses the use of 1-(2-methoxyphenoxy)-3-aminopropan-2-ol as an intermediate in ranolazirle preparation.
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PCT application WO2006008753 disclosed polymorphic Form A of ranolazine, and its process.
1-(2-Methoxyphenoxy)-2,3-epoxypropane of Formula II (epoxide intermediate) can be prepared by the reaction of 2-methoxyphenol with epichlorohydrin in presence of a phase transfer catalyst. This requires a biphasic solvent system consisting of an organic phase and an aqueous phase. When epoxide intermediate is formed there is always the formation of hydroxyl dimer impurity of Formula III which results the lower yield of epoxide intermediate.

Formula III While working on the process of ranolazine the inventors have found epoxide intermediate could be prepared with higher yield and purity in absence of solvent. The process involves the use of a phase transfer catalyst in solvent-free conditions to obtain epoxide intermediate.
In one of the aspect of present invention there is provided a process for the preparation of ranolazine epoxide intermediate of formula II,

Formula II the process includes steps of,
a) reacting 2-methoxyphenol with base to get phenoxide ion,
b) reacting the solution obtained in step a) with epichlorohydrin in presence of a phase transfer catalyst
c) isolating compound of formula II from the reaction mixture thereof.
j

Embodiments of the invention include one or more of the following features. For example, the process is carried out in one pot and isolated epoxide intermediate is purified by vacuum distillation to minimize the concentration of dimmer impurity of Formula III to 5% or below and increase the purity to 97% or more when measured by HPLC.
The 2-methoxyphenol is treated with the aqueous solution of base to get phenoxide ion which on condensation with epichlorohydrin in presence of phase transfer catalyst yields the epoxide compound of Formula II. After completion of reaction it is extracted with suitable organic solvent which on concentration under reduced pressure yields epoxide compound. The epoxide compound is further purified by distillation under reduced pressure to get epoxide having purity 97 % or more when measured by HPLC. The epoxide compound of formula II is used for the synthesis of ranolazine by the method known in the art e.g. U.S. Patent No. 4,567,264.
The term no solvent or absence of solvent means the reaction is conducted in absence of organic solvent.
Non-limiting examples of the base may include one or more of sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, potassium t-butoxide, sodium methoxide and potassium methoxide.
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,
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benzyltrimethylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium acetate, and tetrabutylammonium iodide.
The suitable organic solvents mean the solvents which are immiscible with water such as halogenated solvent, esters, ethers and aromatic solvent which includes for examples methylene chloride, chloroform, carbon tetrachloride, 1,1,1-trichloroethylene, 1,1,2-trichloroethylene, ethyl acetate, butyl acetate, diethyl ether and toluene.
The distillation under reduced pressure to purify epoxide and to reduce the concentration of dimmer impurity involves the high vacuum up to 4 mm of Hg and temperature between 90°C to 140°C.
The invention has been described with reference to various specific and preferred embodiments and techniques which are provided merely to be exemplary of the invention and do not limit the scope of the invention. It should be understood that many variations and modifications will be apparent to those skilled in the art while remaining within the spirit and scope of the invention and all such modifications and equivalents are intended to be included within the scope of the present invention. All patents, patent applications, and literature cited in the specification are hereby incorporated by reference in their entirety. In the case of any inconsistencies, the present disclosure, including any definitions therein will prevail.
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Example 1: Preparation of 1-f2-methoxvphenoxv)-2,3-epoxypropane
To the aqueous solution of sodium hydroxide (39 g sodium hydroxide in 300 ml of water), 2-Methoxyphenol (100 g) was added and stirred at 30-35 °C for 30 minutes. The stock solution was added into the solution of epichlorohydrin (440 g,) and benzyl tri ethyl ammonium chloride (BTEAC) (74 g,) slowly in 4-5 hrs at 30-35 °C. The reaction was stirred at same temperature for one hour. After completion of the reaction, the reaction mass was diluted with water (200 ml) and extracted in methylene chloride. The methylene chloride layer was concentrated and the product is further purified by high vacuum distillation. The pure fraction was collected at 120-138 °C of vapor temperature at 2-4 mm/ Hg.
Yield: 105 g
Purity: >97 % by HPLC
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1. A process for the preparation of 1-(2-methoxyphenoxy)-2,3-epoxypropane of formula II, an useful intermediate for the preparation of ranolazine


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