FIELD OF THE INVENTION
The. present invention relates to an improved process for preparation of Ranolazine wherein the key intermediate i.e. N-(2, 6-dimethylphenyl)-l-piperazine acetamide is not isolated / purified and in situ prepared N-(2, 6-dimethylphenyl)-l-piperazine acetamide intermediate is reacted with l-Methoxy-2-(oxiranylmethoxy) benzene to obtain Ranolazine in high yield and purity.
BACKGROUND OF THE INVENTION
Ranolazine, as represented by the Formula I is chemically known as N-(23 6-dimethyl phenyl)-4-[2-hydroxy-3-(2-methoxy phenoxy) propyl]-1-piperazine acetamide, and found useful as antianginal agent. Ranolazine is indicated for the treatment of chronic anginal. Ranolazine has antianginal and anti-ischemic effects and is marketed under the trade name Ranexa. It is available for oral administration as film^coated, extended-release tablets containing 500 mg or 1000 mg of. Ranolazine;
Formula I
Ranolazine was first disclosed in US 4,567,264 which also describes its preparation by condensing N-(2, 6-dimethylphenyl)-l-piperazine acetamide with l-(2-methoxy phenoxy)-2, 3-epoxypropane. The Ranolazine was obtained in 75-80% purity, which was further purified by column chromatography and was isolated as an oil.
The patent publication US 2009/0318697 describes a process for preparing purified Ranolazine, which is indicated for the chronic treatment of angina, comprising reacting l-[(2,6-dimethylphenyl) amino carbonyljpiperazine with l-phenoxy-2,3-epoxypropane in an inert solvent followed by precipitating the Ranolazine.

EP 0483932 describes the preparation of Ranplazine base by condensation of alpha-[N, N-bis (2-chloroethyl)-amino]-2, 6-dimethylacetanilide with l-[3-(2-methoxy phenoxy)-2-hydroxy]-propyl amine. The crude Ranolazine was further purified by column chromatography and is isolated as an oil.
The PCT application WO 2010/025370 describes the process for the preparation of Ranolazine, wherein the process comprising reacting 2-methoxyphenol with Epichlorohydrine, in the presence of a base, to provide l-(2-methoxyphenoxy)-2, 3-epoxypropane, that is converted to Ranolazine.
The PCT application WO 2010/023687 describes an improved process for the preparation of Ranolazine, pharmaceutical^ acceptable salts and intermediates thereof Specifically it relates to processes for preparation of l-(2-methoxy phenoxy)-2, 3-epoxy propane in substantially aqueous solvent medium and 2-chloro-N-(2, 6-dimethylphenyl) acetamide without using any additional base, which are intermediates, useful in the preparation of Ranolazine.
The PCT application WO 2008/0139492 describes same process for the preparation of Ranolazine as described in product patent US 4,567,264. It further describes . purification method that involves preparation of acid, addition, salt of Ranolazine with fumaric acid, crystallization of the salt obtained followed by neutralization to give pure Ranolazine. *
The PCT application WO 2008/047388 describes the crystallization methods for Ranolazine base from alcohols. The most preferred alcohol being ethanol and the purity of pure Ranolazine obtained by crystallization is 99.49%.
The PCT application WO 2006/008753 describes a process for the preparation of Ranolazine by reacting l-(2-methoxyphenoxy)-2,3- epoxy propane with anhydrous piperazine in methanol, to get l-[3-(2-methoxy phenoxy)-2-hydroxypropyl]: piperazine. This compound is reacted with [(2, 6-dimethylphenyl) amino carbonyl

methyl] „ chloride in anhydrous potassium carbonate and sodium iodide, in Dimethylformamide to get Ranolazine hydrochloride.
The publication, Moen et al, Biocatalysis and Biotransformation, January-February 2005, 23 (1); 45-51 describes the purification of Ranolazine by flash-chromatography using methanol- ether as a solvent.
The prior art methods discussed above suffer from the following disadvantages: a) the Ranolazine is obtained as an oil which is difficult to handle on large scale, b) prior art method uses fumaric acid, leading to multi-step process and hence increases the time cycle, decreases the yield that overall increases the cost, c) Laborious chromatographic techniques are used for purification of Ranolazine and d) crystallization methods known in the prior art provides Ranolazine in relatively lower purity.
Furthermore, most of the prior art processes involve isolation and purification of its key intermediate i.e. N-(2, 6-dimethylphenyl)-l-piperazine acetamide that makes process costly and time consuming. Further, while isolating N-(2, 6-dimethylphenyl)-I-piperazine acetamide during removal of solvent, impurities may be formed which leads to low yield and less purity of Ranolazine.
Based on the drawbacks of the prior art, the present invention is focused towards the preparation of Ranolazine by a simple and cost effective way. Further the present invention is focused to develop a process that involves less number of steps for the preparation of Ranolazine and hence involves less toxic reagents and solvents and hence making process environmental friendly.
Moreover, present invention is focused on isolation of highly pure Ranolazine.

OBJECT OF THE INVENTION
Main object of the present invention is to develop an improved process for the
preparation of Ranolazine that involves iess number of steps,and is environmental
friendly. ' , •
Another object of the present invention is to develop a simple and economically favorable process for the preparation of Ranolazine.
Another object of the present invention is to develop an improved process for purification of Ranolazine wherein said Ranolazine is isolated-with high purity.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of Ranolazine with high purity.
Accordingly, in main aspect, the present invention provides a process for
preparation of Ranolazine comprising the steps of: - a) reacting Piperazine of Formula II with 2-chloro-N-(2,6-dimethylphenyl)-acetamide of Formula III in a suitable solvent, optionally in presence of an acid to obtain N-(2,6-dimethylphenyl)-l-piperazine acetamideof Formula IV,

H
N.
O
N H

+

Formula II Formula III

Formula IV

and b) insitu reacting N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula IV with l-Methoxy-2-(oxiranylmethoxy) benzene of Formula V to obtain Ranolazine of Formula I,

H
H

0 l\^NH
Formula IV

0
X)
Formula V

O

O k^N. Formula I

OH

,0
X)

In other aspect,, the present invention provides a process for preparation of
Ranolazine comprising the steps of:
a) reacting Piperazine of Formula II with 2-chloro~N-(2,6-dimethylphenyl)-acetamide of Formula III in a suitable solvent, optionally in presence of an acid to obtain N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula IV,



NH
H
.N
O:
N H

+

Formula II Formula III

Formula IV

b) insitu reacting N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula IV with l-Methoxy-2-(oxiranylmethoxy) benzene of Formula V to obtain Ranolazine of Formula I,

O ^NH
Formula IV

+

•o
Formula V

X)
- K^K o ^N^I^O
Formula I

and
c) purifying Ranolazine of Formula I.
In another aspect, the present invention further provides a process for preparation of Ranolazine comprising4he steps of:
a) converting crude Ranolazine to its acid addition salt in presence of ketonic solution of an acid and one or more organic solvent;
6

b) filtering the acid addition salt of Ranolazine;
c) adding solvient comprising of at least one ketonic solvent to the acid addition salt of Ranolazine of stepN b) and heating at 40-60°C;
d) filtering to get a wet cake;
-e) adding hydrocarbon solvent to the wet cake of step d) and adjusting the pH to 10
or above by adding a base;
fj heating at 40-60°C;
g) distilling the hydrocarbon solvent to get a solid mass;
h) adding aprotic solvent to the solid mass of step g) and heating at 40-60°C;
i) filtering to get a filtrate; and
j) cooling the filtrate to get precipitates, filtering the precipitates and drying to get
Ranolazine with purity above 99.9%.
FIGURES J
Fig.l represents the X-ray powder diffraction (XRD) pattern of Ranolazine of
Formula I.
Fig. 2 represents the Differential Scanning Calorimetry of Ranolazine of Formula
I.
DESCRIPTION OF THE INVENTION
The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it
is not intended to limit the invention to the particular forms disclosed, but on the
i
- contrary, the invention is to cover all modifications, equivalents, arid alternative falling within the scope of the invention as defined by the appended claims.
The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure. the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.

Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and no'n-limitihgrexamples.
Accordingly, in one embodiment, the present invention provides an improved process for preparation of Ranolazine with high purity.
In other embodiment, the present invention provides a process for preparation of
Ranolazine comprising the steps of:
a) reacting Piperazine Formula II with 2-chloro-N-(2,6-dimethylphenyl)-acetamide of Formula III in a suitable solvent, optionally in presence of an acid to obtain N-(2,6-dimethyIphenyl)-l-piperazine acetamide of Formula IV.


H
N.
+
c
N' H
Formula II Formula III

H \ 0 S/NH
Formula IV


and

b) insitu reacting N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula IV with l-Methoxy-2-(oxiranylmethoxy) benzene of Formula V to obtain Ranolazine of Formula I,
H

^o
O
0
+
O k NH

k0
Formula IV
o k N^A^O
Formula V
Formula I

In another embodiment, N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula IV obtained in step a) is not isolated/purified and the reaction mass

obtained from step a) comprising the product is directly reacted with l-Methoxy-2-(oxiranylmethoxy) benzene of Formula V.
In one another embodiment, the solvent used in step a) is selected from the group comprising of protic solvent such-as alcoholic solvent, selected from methanol, ethanol, isopropanol, butanol; inorganic solvents such as water or mixture thereof.
In a preferred embodiment, the condensation of piperazine with 2-chloro-N-(2,6-dimethylphenyl) acetamide is carried out in absence of any base.
In another embodiment, the condensation of piperazine with 2-chloro-N-(2,6-dimethylphenyl) acetamide may be carried out in presence of acid selected from concentrated hydrochloric acid, phosphoric acid, sulfuric acid, and preferably the acid is concentrated hydrochloric acid.
In a preferred embodiment, when the condensation of piperazine with 2-chloro-N-
(2,6-dimethylphenyl) acetamide is carried out in presence of acid, then preferred
solvent is water. ' x
In another embodiment, the present invention relates to a process for preparation of Ranolazine comprising the steps of:
a) reacting piperazine of Formula II with 2-chloro-N-(2,6-dimethylphenyl)-acetamide of formula III in a suitable.solvent optionally in presence of an acid under heating conditions;
b) filtering the reaction mass to get a filtrate;
c) optionally adjusting the pH of filtrate to 10 or above;'
d) extracting filtrate with dichloromethane;
. e) adding l-Methoxy-2-(oxiranylmethoxy)benzene of Formula V to the
dichloromethane of step d) to obtain a reaction solution; f) distilling dichloromethane with simultaneous addition of solvents comprising mixture of isopropanol and toluene to the reaction solution, to maintain the
M.. 30;-8i- 2:0-:l-8\ IS. : 5 7'9 • '

solvent level in range of 5-8 V of total reaction solution at a temperature in the
range of 40-65°C; g) isolating Ranolazine of Formula I; and h) optionally purifying Ranolazine of Formula I.


Y^^
o
The reaction scheme is described herein below:
H
.N.
. CI
alcohol/dichloromethane
N ' H
or acid/water

NH

Formula II Formula III

Formula IV

O
o
dichloro'methane, IPA:toluene

X)

, Formula V

In one another embodiment, the solvent used in step a) is selected from the group comprising of protic solvent such as alcoholic solvent, selected from methanol, ethanol, isopropanol, butanol; inorganic solvents such as water; or mixture thereof
In a preferred embodiment, the condensation of piperazine with 2-chloro-N-(2,6-dimethylphenyl) acetamide is carried out in absence of any base.
In another embodiment, the condensation of piperazine with 2-chloro-N-(2,6-dimethylphenyl) acetamide may be carried out in presence of acid selected from concentrated hydrochloric acid, phosphoric acid, sulfuric acid, and preferably the acid is concentrated hydrochloric acid.

In a preferred embodiment, when the condensation of piperazine with 2-chloro-N-(2,6-dimethylphenyl) acetamide is carried out in presence of acid, then preferred solvent is water.
In one another embodiment, the pH of the filtrate in step c) is adjusted to 10 or above, by adding aqueous solution of sodium hydroxide.
In another embodiment, the dichloromethane layer in step f) is distilled with simultaneous and continuous addition of mixture of solvents such as IPA and toluene.
In a preferred embodiment, the dichloromethane layer in step f) is distilled with
simultaneous and continuous addition of mixture of solvents such as IPA and
toluene in such a way that the reaction mass remains in a solution form without
isolation of any solid material. ,
In further embodiment, the piperazine of compound of Formula II used for preparation of Rariolazine can be anhydrous in nature.
In other embodiment, the present invention provides a process for preparation of
Ranolazine comprising the steps of:
a) reacting Piperazine of Formula II with 2-chloro-N-(2,6-dimethylphenyl)-acetamide of Formula III in a suitable solvent, optionally in presence of an acid to obtain N-(2:,6-dimethylphenyl)-l-piperazine acetamide of Formula IV,

+
N ^^ O
c

H
N.

Formula II Formula III

Formula IV

b) jhsitu reacting N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula IV with l-Methoxy-2-(oxiranylmethoxy) benzene of Formula V to obtain Ranolazine of Formula I,
l^J\ 0 ^N^A^0
Formula V Formula I
NH
Formula IV

9 •°^>0 ' '(rVrVi ?«

and ~ '
c) purifying Ranolazine of Formula I.
In another embodiment, the present invention provides a process for preparation of Ranolazine which further comprises the steps of:
a) converting crude Ranolazine to its acid addition salt in presence of ketonic solutiqn of an acid and one or more organic solvent;
b) filtering the acid addition salt of Ranolazine;
c) adding solvent comprising of at least one ketonic solvent to the acid addition salt of Ranolazine of step b) and heating at ,40-60°C;
d) filtering to get a wet cake;
e) adding hydrocarbon solvent to the wet cake of step d) and adjusting the pH to 10 or above by adding a base;
f) heating at 40-60°C;
g) distilling the hydrocarbon solvent to get a solid mass;-
h) adding aprotic solvent to the solid mass of step g) and heating at 40-60°C; i) filtering to get a filtrate; and
j) cooling the filtrate to get precipitates, filtering the precipitates and drying to get' Ranolazine with purity above 99.9%.
In one another embodiment, the crude Ranolazine free base may be converted to the acid addition salts by treating with the appropriate organic or inorganic acid, such as, phosphoric, pyruvic, hydrochloric, sulfuric acid and the like.
5B;-ii:-2.e-18- -I.fi ::"5:7^2

In a preferred embodiment, the said organic and inorganic acid is added to
Ranolazine free base in form of ketonic solution of acid wherein the ketone used is
acetone. ■ i '
In one another embodiment, the free base of Ranolazine is dissolved in an organic solvent selected from the group comprising of ethanol, methanol, isopropanol, acetone, methyl isobutyl ketone and mixture thereof; followed by addition of the acid to form Ranolazine acid addition salt.
In a preferred embodiment, the organic solvent is selected from the group comprising of ethanol, methanol, isopropanol, acetone, methyl isobutyl ketone and mixture thereof, and more preferably the solvent used is acetone and methanol.
In one another embodiment, the acid addition salt of Ranolazine is added to a solvent wherein said solvent is present either as a single organic solvent or a combination of more than one organic solvent wherein at least one solvent is ketone such as acetone.
In a preferred embodiment, the solvent used in step c) is selected from the group comprising of ethanol, methanol, isopropanol, acetone, methyl isobutyl ketone and mixture thereof, and more preferably the solvent used is acetone.
In one another embodiment, the pH of the filtrate in step e) is adjusted to 10 or above, by adding aqueous solution of sodium hydroxide.
Moreover, the hydrocarbon solvent used to dissolve wet cake obtained from step e) is selected from the group comprising of toluene, xylene, and preferably, toluene.
Further, the protic solvent used in step h), to dissolve the solid mass obtained after distillation of toluene is selected from the group comprising of methanol, ethanol,
r
.1 3&.-&1- ZB1&- 16. : 5? 13

butanol and isopropanol. In a preferred embodiment, the protic solvent used is methanol.
Further, the precipitates filtered, in step j) are washed with chilled methanol followed by drying to get pure Ranolazine.
In a preferred embodiment, the Ranolazine is isolated in step j) with purity above 99%, preferably above 99.5%), and more preferably above 99.9%. '
In a preferred embodiment, the Ranolazine, isolated in step j) is free, or substantially free, of potential genotoxicity wherein 2-((2-methoxyphenoxy)methyl)oxirane (Formula V) and / or epichlorohydrine is present in an amount equal to or less than about 0.05% relative to Ranolazine.
In further embodiment, the Ranolazine isolated in step j) is free, or substantially free of impurities represented by impurity of Formula B, dimer impurity of Formula D, Dimer impurity of Formula E, impurity of Formula F, Impurity of Formula G and Impurity of Formula H, N-oxide Impurity of Formula M as represented below; wherein said impurities are present in an amount equal to less than about 0.5%), or less than about 0.3%, or less than about 0.1 %, or less than about 0.05%, or less than about 0.01%, or less than about 0.005%), or less than about 0.001%, by weight, of each individual impurity.

Impurity B

*B- 0:1--2:018 •

14



Dimer Impurity D

Dimer Impurity E

CIN^^CI


Impurity F

Impurity G

Impurity H

Impurity M

In pne another embodiment, the Ranolazine of Formula I is characterized by XRPD peaks at 4.95, 9.92, 10.30, 10.60, 12.17, 12.42, 13.02, 14.28, 14.9l| 15.46, 15.95, 16.43, 16.86, 17.41, 17.84, 19.28, 19.74, 20.37, 20.65, 21.35, 22.33, 23.36, 24.02, 24.60, 24.96, 25.42, 2i5.14, 26.43, 27.17, 27.42, 27.84, 28.65, 30.06, 30.25, 31.07, 31.74, 32.25, 32.53, 33.17, 33.52, 33.91 and 34.44 ±0.2°9.
In one another embodiment, the Ranolazine of Formula I is characterized by DSC with endotherm peak at 120.36°C.

31

1:1.-' 2.

■7

15.

'
In one another embodiment, the Ranolazine is characterized with purity aboye 99%, preferably above 99.5%, and more preferably above 99,9%.
In one another embodiment, the present invention further provides a composition comprising Ranolazine and one or more pharmaceutical acceptable excipients.
In one another embodiment, the present invention further provides a stable
i
Ranolazine wherein said Ranolazine is stable.at 40°C:± 2°C / 75% ± 5%(RH).
In another embodiment, the stable Ranolazine of Formula I may be characterized by at least 2 months stability results as outline in Table-! which is representative for one of the batch.
Table-1

S. No Parameters Initial 1 month 2 month Spec Limit
.1 Description White powder White powder White powder White to off white powder
2 LOD (%w/w, dry
at 80°C for 3 hrs,
u/v) ' 0.28 0.27 0.21 Not more than 0.5
3 Impurity Profile
3.1 Total Impurities 0.06 0.07
r 0.10 NMT1..0'
32 Assay 98.4 99.6 99.9 . NLT 98.0 and NMT 102.0
ND= Not detected, NLT= Not less then, NMT=Npt more than

No degradation observed under specified condition up to 2 months.
In further embodiment, the present invention provides Ranolazine of Formula I characterized by particle size distribution wherein, d90 is between 0.1 \xm to 200|im.
In a preferred embodiment, the Ranolazine of Formula I is characterized by particle size distribution wherein, dgo is between 2.0 \xm to 150(am.
The embodiments of the present invention are exemplified herein below:
EXAMPLES:
Example 1: Preparation of 2-((2-methoxyphenoxy)methyl)oxirane (Formula
V)


&

OH CI

Formula V
40 g (2.5 mol) NaOH was dissolved in 300 ml DM water and cooled to 30-35°C. Charged lOOg (2.014mol) of 2-methoxy phenol and stirred for 60-120 min at 20-25°C and added 298 g (8.045mol) of 2-(chloromethyl)oxirane (Epichlorohydrine) and 45 ml of 1, 4-Dioxane at 20-25°C. The reaction mass was stirred at 25-30°C till completion of reaction. After completion of the reaction, separated the layers. Washed the organic layer with DM water and distilled out the Epichlorohydrine from the reaction mass at 85°C under vacuum. The Oil mass thus obtained was then distilled at high vacuum at between 130rl 80°C to collect the pure product from the reaction mass.
Yield: 68% . . ^
Purity: 95.0 %
17

Example 2: Preparation of 2-chloro-N-(2, 6-dimethyIphenyl)-acetamide (Formula III)
2,6-dichloroaniline (350 g, 2.88mol) was dissolved in Dichioromethane and cooled under stirring at 0°C. Chloroacetyl chloride (457 g, 4.0 mol) was added to the reaction mass under stirring at a temperature between 0°C to 25°C. The reaction mass was stirred at between 0°C to 25°C for 30 min. After -completion of the reaction, aqueous sodium hydroxide was added to the reaction mass under stirring at 0°C to 25°C to adjust the pH to 10-12. Separated the organic layer and aqueous layer was extracted with Dichioromethane. Dichioromethane layer was washed with DM water^and was distilled out under reduced pressure. Recrystallized the compound so obtained with Cyclohexane. The product was filtered and washed with Cyclohexane to give wet product which was then dried in an oven at 50-55°C. Yield: 97% Purity: 99.44 %
Example 3: Preparation of Ranolazine by feactingl-Methoxy-2-(oxiranylmethoxy) benzene of Formula V and N-(2, 6-dimethylphenyl)-l-piperazine acetamide of Formula IV (without isolating compound of formula IV)
Piperazine anhydrous (54.5 g) and methanol (75 ml) was added in a RBF. To the reaction was added 2-chloro-N-(2, 6-dimethylphenyl)-acetamide (25 g) at 10-20°C and stirred the reaction mass at 20-30 °C for 2 hrs. After completion of the reaction^ added DM water into the reaction mass. Filtered the reaction mass through hyflow bed and the bed washed with DMW. Dichioromethane (MDC) was xadded to the filtrate, stirred and separated the aqueous layer. The aq. layer was extracted with 50 ml MDC. MDC layer was collected together and washed with DMW. MDC layer was charged into RBF, charged 17.5g l-Methoxy-2-(oxiranylmethoxy)benzene at 20- 23 °C, further distilled out dichioromethane with simultaneous addition of mixture of IPA and toluene to maintain the solvent level of the reaction solution up to 5V without isolation of any solid mass. Stirred the reaction solution at 50-55°C
■£-, S6-8:l,- Z0/1.8.'' !■■& ■ 5 718 , " - .

for 1-2 hrs. After completion of the reaction cooled the reaction mass to 20-30°C under continuous stirring. Filtered the product and washed the solid so obtained with mixture of chilled Isopropyl alcohol and Toluene to get crude solid of Ranolazine.
Example 4: Preparation of Ranolazine by reacting l-Methoxy-2-(oxiranylmethoxy) benzene of Formula V and N-(2, 6-dimethylphenyl)-l-Piperazine acetamide of Formula IV (without isolating compound of formula IV)
To 393g of Piperazine was added 4V of DM water followed by addition of concentrated hydrochloric acid to adjust the pH to 6.6-6.9. Added 300g of 2-chloro-N-(2, 6-dimethylphenyl)-acetamide and raised the temperature to 90-95°C. Stirred the reaction at 90-95°C till completion of reaction. Cooled the reaction mass and filtered the reaction mass through hyflow bed. Washed the solid so obtained with DM water and collected the filtrate. Charged 5V of Dichloromethane and added aqueous solution of sodium hydroxide to adjust the pH of aqueous layer to above 10. Stirred the reaction solution so obtained and allowed to settle down the layers. Separated the organic and aqueous layer and added l-Methoxy-2-(oxiranylmethoxy) benzene of Formula V to the dichloromethane layer. Stirred the solution and then distilled the dichloromethane layer with simultaneous addition of mixture of IP A and toluene in order to maintain the solvent level of the reaction solution up to 5V without isolation of any solid mass and stirred the reaction solution so obtained at6 0T65°C till completion of reaction. After completion of reaction cooled the reaction mass and filtered the solid material and washed the solid with IPA. Dried the solid so obtained to get crude mass of Ranolazine.
Example 5: Purification of Ranolazine
Crude Ranolazine obtained from example 3 or 4 was dissolved in MDC and charged DMW. Added cone. HC1 (about 15-20 ml) to adjust the pH to 1-2. Stirred the reaction mass at 20-30°C then separated organic layer and aqueous Layer washed with MDC. Aqueous Layer charged into the RBF and added MDC and adjusted the

pH to 10-12 with NaOH solution. Stirred the reaction mass at 20-30°C then separated organic layer. Distilled out MDC layer under reduced pressure and removed traces completely. Charged Methanol into the residue and stirred at 50-55°C to dissolve the material, charged 2.3g activated carbon. Stirred the reaction mass, then filtered through hyflow bed and filtrate collected and cooled the mass to 20-30°C and stirred for 2.0 hours, further cooled the reaction mass to 5-10°C and stirred. The product was filtered and washed with chilled Methanol to give wet product which was then dried in an oven at 50-55°C to give pure Ranolazine. HPLC purity: 99.9 %
Example 6: Purification of Ranolazine
Crude Ranolazine obtained from example 3 or 4 was dissolved in 1.5 V of methanol and 2V of acetone. Prepared the\solution of 270.Og of sulfuric acid in 900 ml acetone and added the acetonic sulfuric acid to the above solution of Ranolazine. Added 8V of acetone and heated the solution so obtained to 55-60°C under stirring for lh. Cooled the reaction mass and filtered with washing the solid so obtained with acetone. To the wet solid so obtained was added 7V of acetone and stirred. Cooled the reaction mass and filtered followed by washing with acetone to get wet cake. To the wet cake so obtained was added toluene followed by addition of 5 V of aqueous sodium, hydroxide solution to adjust the pH to 10-12 under stirring and then separated the layers. Washed the toluene layer with DM water and concentrated to get a solid mass. To the solid mass so obtained was added 4.5 V of methanol under heating at 55-60°C to get clear reaction mass. Filtered the reaction mass through filter paper and washed the undesired solid with hot methanol. Collected the filtrate and then cooled under stirring. Filtered the precipitates so
s
obtained and washed the precipitates with chilled methanol. Dried the precipitates under 50-55°C to get pure Ranolazine. HPLC purity: 99.9 %

We Claim:
1. A process for preparation of Ranolazine comprising the steps of:
a) , reacting Piperazine of Formula II with 2-chloro-N-(2,6-dimethylphenyl)-acetamide of Formula III in a suitable solvent, optionally in presence of an acid to obtain N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula IV,



NH
H
O
N H

+

Formula II Formula III

Formula IV

and
b) insitu reacting N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula IV with l-Methoxy-2-(oxiranylmethoxy) benzene of Formula V to obtain Ranolazine of Formula I,

Formula IV

O^A
Formula V

Formula I

2. The process as claimed in claim 1, wherein said N-(2,6-dimethylphenyl)-l -piperazine acetamide of Formula IV obtained in step a) is not isolated.
3. The process as claimed in claim 1, wherein said solvent used in step a) is selected from the group comprising of methanol, ethanol, isopropanol, butanol, water or mixture thereof.
\ •
4. The process as claimed in claim 1, wherein said acid is selected from
concentrated hydrochloric acid, phosphoric acid and sulfuric acid.
5. The process as claimed in claim 1, wherein said process comprises the steps of:

a) reacting piperazine of Formula II with 2Tchloro-N-(2,6-dimethylphenyl)-acetamide of formula III in a suitable solvent optionally in presence of an acid under heating conditions; N
b) filtering the reaction mass to get a filtrate;
c) optionally adjusting the pH of filtrate to 10 or above;
d) extracting filtrate with dichloromethane;
e) adding l-Methoxy-2-(oxiranylmethoxy)benzene of Formula V to the dichloromethane of step d) to obtain a reaction solution;
f) distilling dichloromethane with simultaneous addition of solvents comprising mixture of isopropanol and toluene to the reaction solution, to maintain the solvent level in the range of 5-8V of total reaction solution at a temperature in the range of 40-65°C;
g) isolating Ranolazine of Formula I; and
r
h) optionally purifying Ranolazine of Formula I.
>. A process for preparation of Ranolazine comprising the steps of:
a) reacting Piperazine of Formula II with 2-chloro-N-(2,6-dimethylphenyl)-
acetamide of Formula III in a suitable solvent, optionally in presence of an
acid to obtain N-(2,6-dimethylphenyl)-l-piperazine acetamide of Formula
_ IV,

Y~0
0 •