FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
A PROCESS FOR THE PREPARATION OF 2-((1,3-BIS(2-METHOXYPHENOXY)PROPAN-2-YLOXY)METHYL)OXIRANE
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 invention provides a process for the preparation of 2-((1,3-bis(2-methoxyphenoxy)propan-2-yioxy)methyl)oxirane.
The following specification particularly describes the invention and the manner in which it is to be performed.

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4. DESCRIPTION

The invention provides 2-((1,3-bis(2-methoxyphenoxy)propan-2-
yloxy)methyl)oxirane and its process for the preparation. It is further characterized by its 1H NMR, 13C NMR, Mass and IR spectral data.
Ranolazine of Formula I is chemically known as (±)N-(2,6-Dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide. It is commercially available under the trade name Ranexa®. Ranolazine has been used as anti¬anginal and anti-ischemic agent without reducing heart rate or blood pressure.

OH OMe
FORMULA I
U.S. Patent No. 4,567,264 discloses about the synthesis of Ranolazine base by condensing [(2,6-dimethylphenyl)-amino carbonyl methyl]-chloride with 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-piperazine.
European Patent No. 0,483,932 describes the process of preparation of Ranolazine by condensation of 1-[3-(2-methoxyphenoxy)-2-hydroxy]-propylamine with a-[N,N-bis-(2-chloroethyl)-amino-2,6-dimethylacetanilide hydrochloride.
PCT application 2008/047388 discloses improved process for the preparation of Ranolazine base and Ranolazine hydrochloride.
PCT application 2006/008753 discloses about the crystalline and amorphous Form of Ranolazine base and Ranolazine hydrochloride and their method of preparation.
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The inventors while developing a process for the preparation of Ranolazine have identified the compound of Formula II e.g. 2-((1,3-bis(2-methoxyphenoxy)propan-2-yloxy)methyl)oxirane present in the Ranolazine. Further, they developed a process for its preparation. 2-((1,3-bis(2-methoxyphenoxy)propan-2-yloxy)methyl)oxirane of Formula II shows a HPLC purity of 95% or more.

In one aspect of the invention there is provided a process for the preparation of 2-((1,3-bis(2-methoxyphenoxy)propan-2-yloxy)rnethyl)oxirane, which includes the steps of:
o-
OMe MeO
FORMULA II
a) treating 1,3-bis(2-methoxyphenoxy)propan-2-ol of Formula III with
2(substituted methyl) oxirane compound of Formula IV,

OH .0-

FORMULA III

FORMULA IV

wherein substituted X is selected from the group of F, CI, Br, I, mesyl and tosyl.
b) isolating 2-((1,3-bis(2-methoxyphenoxy)propan-2-yloxy)methyl)oxirane of Formula II from the reaction mixture thereof.
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2-((1,3-bis(2-methoxyphenoxy)propan-2-yloxy)methyl)oxirane of is prepared by treating 1,3-bis(2-methoxyphenoxy)propan-2-ol with 2(substituted methyl) oxirane in presence of base and phase transfer catalyst in the suitable solvents. The reaction mixture is stirred at 40- 60 °C. After completing the reaction the reaction mixture is quenched with water. The reaction mass was neutralized with acid and the product is isolated from the reaction mass thereof.
2-((1,3-bis(2-methoxyphenoxy)propan-2-yloxy)methyl)oxirane of Formula II is further characterized by its 1H NMR, 13C NMR, Mass and IR spectral data.
1H NMR (400 MHz, CD3OD): 5 6.84- 7.02 (8H, m), 4.20- 4.28 (2H, m), 4.08- 4.20 (3H, m), 3.98- 4.04 (1H, m), 3.79 (6H, s), 3.62- 3.70 (1H, m), 3.15- 3.22 (1H, m), 2.72- 2.78 (1H, m), 2.62- 2.66 (1 H,m).
13C NMR(75MHz, CD3OD): 150.0, 148.6,121.7, 121.0, 114.5, 112.5,77.6,71.5, 69.2, 55.3, 50.9, and 43.8.
Mass: (m/e)= 361.1 (M+1).
IR (KBr,CM-1)= 3063, 3003, 2934, 2836, 2891, 1590, 1508, 1452, 1438, 1387, 1358, 1330, 1289, 1256, 1225, 1183, 1123, 1076, 1053, 1024, 992, 934, 908.
2-((1,3-bis(2-methoxyphenoxy)propan-2-yloxy)methyl)oxirane, shows HPLC purity 95% or more.
The term isolation includes the isolation of the compound by removal of the solvent from the reaction mixture or addition of antisolvent, filtration, decantation, centrifugation and chromatographic separation.
The bases include the example of primary, secondary and tertiary amines, substituted amines including diethylamine, N-ethylpiperidine, isopropylamine,
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morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine or ammonia; or inorganic bases such as sodium hydride, lithium hydride, potassium hydride, potassium tert-butoxide sodium methoxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide and the like.
The term "phase transfer catalyst" is a catalyst, which facilitates the migration of a reactant in a heterogeneous system from one phase into another phase where reaction can take place.
The term "phase transfer catalyst" includes the example of quaternary ammonium saits or phosphonium salts. The example of quaternary ammonium salts includes salts such as tetrabutylammonium iodide, tetrabutylammonium chloride, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, dimethyl didecyl ammonium chloride, hexadecyl trimethyl ammonium bromide, methyl tributyl ammonium chloride, methyl trioctyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutylammoniumhydrogensulfate, tetraethyl ammonium bromide, tetramethyl ammonium bromide, tetraoctyl ammonium bromide, tetrapropyl ammonium bromide.
The example of phosphonium salts includes salts such as butyl triphenyl phosphonium bromide, ethyl triphenyl phosphonium bromide, ethyl triphenyl phosphonium iodide, hexadecyl tributyl phosphonium bromide, methyl triphenyl phosphonium bromide, tetraphenyl phosphonium bromide.
The term used herein the "suitable solvents" it includes the use of polar aprotic solvent, polar protic solvent or mixture thereof.
The example of polar protic and polar aprotic solvent includes solvents such as water, methanol, ethanol, n-propanol, n-butanof, dimethylformamide,
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dimethylsulphoxide, acetonitrile, dioxane, acetone, tetrahydrofuran or mixture thereof.
2-((1,3-bis(2-methoxyphenoxy)propan-2-yloxy)methyl)oxirane of Formula I! may be used for making pharmaceutical composition in association with a pharmaceutical^ acceptable excipient and/or carrier wherein the composition may comprise formulations such as solid compositions, liquid compositions or other compositions for oral administration or as injections, liniments or suppositories for parenteral administration.
The invention is further illustrated by the following example which is 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 invention.
Example 2-((1,3-bis(2-methoxyphenoxy)propan-2-yloxy)methyl)oxirane:
To the solution of 1,3-bis(2-methoxyphenoxy)propan-2-ol (5 gm) in tetrahydrofuran (50 ml) was added Sodium hydride (0.78 g m) at 0 °C followed by addition of Benzyltriethylammonium chloride (1.49 gm) at the same temperature. To this resulting reaction mixture epichlorohydrin (1.52 gm) was added at room temperature. The reaction mixture was stirred for two hours at room temperature and then for nine hours at 50 °C. The reaction mixture was cooled to 0 °C and quenched with distilled water (50 ml). The reaction mass was neutralized with dilute hydrochloric acid and extracted with dichloromethane (200 ml). Organic layer was separated concentrated and purified over column chromatography (Hexane/ Ethyl acetate; 3:1). Yield: 1.5 gm Purity: 96.87% (HPLC)
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We claim:
1. A compound 2-((1,3-bis(2-methoxyphenoxy)propan-2-yloxy)
methyl)oxirane, of Formula II
o-
2. A process for the preparation of 2-((1,3-bis(2-methoxyphenoxy)propan-2-yloxy)methyl)oxirane, which comprises of:

a) treating 1,3-bis(2-methoxyphenoxy)propan-2-ol of Formula III with 2(substituted methyl) oxirane compound of Formula IV,
OH o

FORMULA III FORMULA IV
wherein substituted X is selected from the group of F, CI, Br, I, mesyi and tosyl.
b) Isolating 2-((1,3-bis(2-methoxyphenoxy)propan-2-
yloxy)methyl)oxirane from the reaction mixture thereof.
3. The process of claim 2, wherein reaction is carried out in solvent
comprises of one or more of hexane, benzene, toluene, xylene,
dimethoxyethane, tetrahydrofuran, dimethylsulfoxide, N,N-
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dimethylformamide, methanol, ethanol, n-propanol, n-butano! , 1,4-dioxane and N,N-dimethyi acetamide.
4. The process of claim 2, wherein reaction is carried out in presence of base comprises of one or more of diethylamine, N-ethylpiperidine, isopropylamine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine or ammonia, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, potassium tert-butoxide, sodium hydroxide, lithium hydroxide and potassium hydroxide.
5. The process of claim 2, wherein reaction is carried out in presence of phase transfer catalyst.
6. The process of claim 5, wherein phase transfer catalyst are quaternary ammonium or phosphonium salts.
7. The process of claim 6, wherein quartemary ammonium or phosphonium salts comprises one or more of tetrabutylammonium iodide, tetrabutylammonium chloride, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, methyl tributyl ammonium chloride, methyl trioctyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulfate, tetraethyl ammonium bromide, tetramethyl ammonium bromide, tetraoctyl ammonium bromide, tetrapropyl ammonium bromide, butyl triphenyl phosphonium bromide, ethyl triphenyl phosphonium bromide, ethyl triphenyl phosphonium iodide, hexadecyl tributyl phosphonium bromide, methyl triphenyl phosphonium bromide, and tetraphenyl phosphonium bromide.
8. A 2-((1,3-bis(2-methoxyphenoxy)propan-2-yloxy)methyl)oxirane having purity 95.5% or more when measured by HPLC.
9. The compound of claim 8, wherein purity is 96.5%.
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10.A Ranolazine dihydrochloride containing 2-((1,3-bis(2-
methoxyphenoxy)propan-2-yioxy) methyl)oxirane in the amount of 1 % or less.
Dated this '" day of July, 2008 For Wockhardt Limited
(Mandaif Kodgule) Authorized Signatory
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