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 SUBSTITUTED 3-ARYLOXY PROPANE DERIVATIVES
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 new process for preparation of substituted 3-aryloxy propane derivatives.
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 a process for preparation of substituted 3-aryioxy propane derivatives. It further provides its characterization by spectral analyses such as IR, NMR and mass.
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 α-[N,N-bis-(2-chloroethyf}-amino-2,6-dimethyiacetanilide 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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There are several processes known for the synthesis of compound of Formula II e.g. Research journal Tetrahedron, 62(47), 10968-10979; 2006, Journal of Medicinal Chemistry, 38(20), 3983-94; 1995, Research Journal Biocatalysis and Biotransformation, 23(1), 45-51; 2005.
The inventors while developing a process for the preparation of Ranolazine have found that compound of Formula II or salts thereof is formed during the preparation of Ranolazine and its salt. It was identified and further characterized by spectral analyses.
In one aspect of the invention there is provided a process for the preparation of compound of Formula II, which includes the steps of:

OH -CL Js. .X
OCH3
FORMULA II
X is independently selected from the group of F, CI, Br or I. a) treating 2-((2-methoxyphenoxy)methyl)oxirane of Formula III with inorganic acid in organic solvent,
Q
OCH3
FORMULA III
b) isolating compound of Formula II from the reaction mixture thereof.

The compound of Formula II was prepared by treating 2-((2-methoxyphenoxy)methyl)oxirane of Formula III with inorganic acids at reflux temperature in organic solvents.
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The compound of Formula II is characterized by 1H NMR, 13C NMR, Mass and IR spectra.
In this disclosure, the term "inorganic acids" refers to acids such as hydrofluoric acid, hydrochloric, hydrobromic and hydroiodic acid.
The term solvent includes solvents such as tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, 1,4-dioxane, methanol, ethanol, propanol, isopropyl alcohol, water or mixture thereof.
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 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 1-Ch1oro-3-(2-methoxyphenoxy)propan-2-ol
To the solution of 2-((2-methoxyphenoxy)methyl)oxirane (4gm) in isopropyl
alcohol (10 ml) was added solution of HCl in isopropyl alcohol (24% WAV, 10 ml)
and the reaction mixture was heated to reflux for one hour. After completing the
reaction solvent was removed and titled product was isolated.
Yield: 4.5 g
Purity = 95.92% (by HPLC)
1H NMR (400 MHz, CD3OD): 6 6.85-6.96(4H,m), 4.08-4.15 (1H, m), 4.01 - 4.04 (2H, m,),3.79 (3H,s), 3.64-3.79 (2H,m).
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13C NMR(75MHz,CD3OD): 149.8, 148.4, 121.9, 121.1, 114.4, 112.4,70.4,69.8, 55.3, 45.7.
Mass: (m/e): 217.1 (M+1).
IR (KBr, cm1): 3445, 2937, 2838, 1593, 1505, 1455, 1329, 1254, 1179, 1125,
1028,829,746
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We claim:
1. A process for the preparation of compound of Formula II, which comprises of:
OH
'OCH3
Formula II X is independently selected from the group of F, CI, Br or I.
a) treating 2-((2-methoxyphenoxy)methyl)oxirane of Formula III with inorganic acid in presence of solvent.
Q
T)CH3
FORMULA III
b) isolating compound of Formula II from the reaction mixture thereof.
2. The process of claim 1a, wherein inorganic acid comprises of one or more of hydrofluoric, hydrochloric, hydrobromic and hydroiodic acid.
3. The process of claim 2, wherein inorganic acid is hydrochloric acid.
4. The process of claim 1 wherein the solvents comprises one or more of tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, 1,4-dioxane, methanol, ethanol, propanol, isopropyl alcohol and water.
5. The process of claim 4, wherein the isopropyl alcohol is used.
6. The process of claim 1, wherein compound is 1-Chloro-3-(2-methoxyphenoxy)propan-2-ol.
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7. A compound 1-Chloro-3-(2-methoxyphenoxy)propan-2-ol having HPLC purity 95% or more.

TH
Dated this __m day of July, 2008

For Wockhardt Limited


%M
(Mandar Kvodgule) Authorized Signatory

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