FIELD OF INVENTION
The present invention provides an improved process for the preparation of ranolazine, of formula I,
(Figure Remove)

OH

Formula I
and pharmaceutically acceptable salts thereof, which is an important antianginal and anti-ischemic agent.
BACKGROUND OF THE INVENTION
Ranolazine, of formula I,
,OCH3
(Figure Remove)

Formula I
is an important antianginal and anti-ischemic agent and is chemically known as l-[3-(2-methoxyphenoxy)-2-hydroxy propyl] -4- [(2,6-dimethylphenyl) aminocarbonyl methyl]piperazine. Ranolazine has been shown to exert its anti-anginal and anti-ischemic effects without reducing heart rate or blood pressure. It does not increase the rate-pressure product at maximal exercise levels.
Ranolazine was first disclosed in United States patent no. 4,567,264. The patent

described two processes for the preparation of ranolazine. The difference between the two processes resides in the fact that the substituent groups on the two nitrogen atom of the piperazine ring are introduced in different sequences.
One of the two processes disclosed in above patent comprises the steps of reacting 2,6-dimethylaniline derivative with chloroacetyl chloride in the presence of triethylamine and methylene chloride to form an amide intermediate, which is reacted with piperazine and the resulting piperazine derivative is further condensed with an appropriate oxirane derivative ( prepared by the reaction of 2-methoxyphenol with epichlorohydrin in the presence of strong base in water and dioxane) in a mixture of two solvents, methanol and toluene and ranolazine is isolated as oil using chromatographic technique and converted to dihydrochloride acid salt using excess of hydrochloric acid.
The major drawbacks of above process are: the use of triethylamine during amide formation as triethylamine is known to be carcinogenic, harmful, and corrosive and may cause damage to liver and mucous membranes. Further the product obtained is dark brown colored compound which require purification and amounts to loss in yield and increase in cost.
The yield and purity of oxirane derivative has not been mentioned in the above patent. In our hands we have found that repetition of exemplified experiment results in large number of impurities, including dimer impurity namely, l,3-bis-(2-methoxy-phenoxy)-propan-2-ol of following formula
(Figure Remove)

alone forms up to 24-25%. We have prepared and characterized this impurity. Removal of this impurity requires costly and time consuming purification steps which make the process expensive and unsuitable for commercial point of view.
During condensation of piperazine derivative with oxirane derivative, mixture of solvents is used and further ranolazine is isolated using column chromatographic technique. Column chromatography is a cumbersome, tedious, expensive, and inconvenient unit operation, which uses in some cases harmful or toxic solvents and therefore it is not an environmental friendly technique, and cannot be advantageously used for industrial large-scale production.
So, in the light of the above description, it is clear that the prior art process for the preparation of ranolazine involves expensive and harmful reagents, stringent reaction conditions and use of column chromatography which is unsuitable for large-scale production. Further the removal of high amount of unwanted impurities formed during the reaction; require multiple purifications and results in low yields.
Therefore it is an urgent need to develop a simple and cost effective process to prepare ranolazine which is easy to implement on industrial scale. It is therefore, an object of the present invention to provide an efficient and industry viable process for preparing ranolazine and its salts in high yield and high purity, avoiding the use of unsafe and expensive reagents and tedious processes like chromatographic techniques.
SUMMARY OF THE INVENTION
Accordingly one embodiment of the present invention provides an improved and industrially advantageous process for the preparation of ranolazine of formula-I and its salts using mild reaction conditions.

JDCH
(Figure Remove)

Formula I
More particularly, the present invention describes an improved, simple and cost effective process for the preparation of l-[3-(2-methoxyphenoxy)-2-hydroxy propyl] -4- [(2,6-dimethylphenyl) aminocarbonylmethyl] piperazine of formula I, and its salts which comprises:
a) reacting 2-methoxyphenol with epichlorohydrin in the presence of base in a suitable organic solvent, using phase transfer catalyst to afford l-methoxy-2-(oxiranyl methoxy)benzene of formula II,
Q X),
(Figure Remove)

Formula II
b) reacting 2,6-dimethylaniline with chloroacetyl chloride in presence of base in water to afford 2-chloro-Ar-(2,6-dimethylphenyl)acetamide of formula III,
(Figure Remove)

Formula III
c) reacting 2-chloro-//-(2,6-dimethylphenyl)acetamide with piperazine in ethanol to form A7-(2,6-dimethyl phenyl)-!-piperazine acetamide of formula IV,

(Figure Remove)

Formula IV
d) condensing vV-(2,6-dimethyl phenyl)-l-piperazine acetamide of formula IV with
l-methoxy-2-(oxiranyl methoxy)benzene of formula II in an inert solvent to form
ranolazine,
e) converting ranolazine to its pharmaceutically acceptable salts by treating with
mineral acid by conventional methods.
In yet another embodiment, the present invention provides a process for the purification of ranolazine by recrystallization with suitable organic solvent such as alcohols or aromatic hydrocarbons.
In yet another embodiment, the present invention provides a process for the preparation of l-methoxy-2-(oxiranyl methoxy) benzene of formula II
.0

(Figure Remove)

Formula II
which comprises reacting 2-methoxy phenol with epichlorohydrin in an organic solvent in the presence of a phase transfer catalyst and base.
In yet another embodiment, the present invention provides a process for the preparation of 2-chloro-N-(2,6-dimethylphenyl)acetamide of formula III

(Figure Remove)

Formula III
which comprises reacting 2,6-dimethylaniline with chloroacetyl chloride in presence of a suitable base in water.
DETAILED DESCRIPTION OF THE INVENTION
The process of this invention is a high throughput process which provides the desired ranolazine of formula I and its salts in high yield and high purity,
(Figure Remove)

Formula I
by condensing l-methoxy-2-(oxiranylmethoxy)benzene of formula II and N-(2,6-dimethyl phenyl)-l-piperazine acetamide of formula IV in the presence of inert solvent and thereafter treating the resulting ranolazine with mineral acid by conventional methods.
One embodiment of the present invention provides an improved and efficient process for preparing l-methoxy-2-(oxiranylmethoxy)benzene of formula II, an important intermediate for the preparation of ranolazine and its salts.

(Figure Remove)

Formula II
The invention encompasses the synthesis of l-methoxy-2-(oxiranylmethoxy)benzene of formula II using atleast one phase transfer catalyst. Generally the reaction of 2-methoxyphenol with epichlorohydrin is carried out in the presence of aqueous base using suitable organic solvent using atleast one phase transfer catalyst.
Typically, the process involves adding an aqueous base to 2-methoxyphenol. Typically, inorganic bases are used which include, alkali metal hydroxides, carbonates and bicarbonates. The alkali metal hydroxides, carbonates, and bicarbonates may be sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like. In particular, the base used is sodium hydroxide. To the above solution, an organic solvent is added followed by the addition of a phase transfer catalyst.
The organic solvent may be water immiscible and one or more of hydrocarbon, chlorinated solvent, or mixtures thereof. The hydrocarbon may include toluene or xylene. The chlorinated solvent may include one or more of dichloromethane, dichloroethane and chloroform.
The phase transfer catalyst may be present in an amount of about 0.05 to about 0.20 mol equivalents to 2-methoxyphenol, and is preferably present in an amount of about 0.05 to about 0.10 mol equivalents to 2-methoxyphenol. Several classes of compounds are known to be capable of acting as phase transfer catalysts, such as quaternary ammonium compounds and phosphonium compounds. Phase transfer catalysts include, but are not limited to, tetrabutylammonium bromide; tetrabutylammonium hydroxide; tricaprylylmethylammonium chloride, dodecyl

sulfate, sodium salt, such as sodium lauryl sulfate; tetrabutyl ammonium hydrogensulfate; hexadecyl tributyl phosphonium bromide; or hexadecyltrimethylammonium bromide. Preferably, the phase transfer catalysts used in the methods of the invention include at least one of the tetrabutylammonium bromide or tetrabutylammonium hydrogensulfate.
Generally, the reaction mixture is stirred for few minutes to few hours at ambient temperature. Preferably, the reaction mixture is stirred for half an hour to 10 hours. To the above reaction mixture epichlorohydrin is added and the reaction mass can be further stirred for few hours at 20-45°C. Preferably, the reaction mixture is stirred for 5 to 6 hours at 30-40°C. The reaction completion is monitored by thin layer chromatography. After completion of reaction, layers are separated and the aqueous layer is extracted with same organic solvent. The combined organic layer is optionally charcoalized and distilled to afford 1 -methoxy-2-(oxiranylmethoxy) benzene as oil which can be used as such in next step. Using phase transfer reaction the formation of dimer impurity namely, l,3-bis-(2-methoxy-phenoxy)-propan-2-ol
of formula V

(Figure Remove)
Formula V
is reduced to about 8 % relative to desired product.
It is advantageous to use phase transfer catalyst in biphasic system over single-phase systems because of an increased reaction rate, decreased reaction temperature, low impurity formation, and high relative purity.

Optionally crude l-methoxy-2-(oxiranyl methoxy)benzene may be purified using high vacuum distillation at 130-150°C at 5 bar pressure to afford highly pure 1-methoxy-2-(oxiranyl methoxy)benzene having dimer impurity of formula V less than 0.30% ratio.
Another embodiment of the present invention provides a simple and efficient process for preparing 2-chloro-jV-(2,6-dimethylphenyl) acetamide of formula III, another crucial intermediate useful for the preparation of ranolazine dihydrochloride,
(Figure Remove)

Formula III
which comprises reacting 2,6-dimethylaniline with chloroacetyl chloride in the presence of aqueous base in the absence of organic solvent.
Particularly 2,6-dimethylaniline is reacted with chloroacetyl chloride in the presence of base in aqueous medium. Typically, inorganic bases are used which include, alkali metal hydroxides, carbonates and bicarbonates. The alkali metal hydroxides, carbonates, and bicarbonates may include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate; preferably the base is sodium bicarbonate. The base may be present in an amount of about 1.0 mol equivalents to about 2.0 mol equivalents. Preferably, the base is present in an amount of about 1.2 to about 1.3 mol equivalents to 2,6-dimethylaniline. It is advantageous to carry out the reaction at lower temperature preferably below 10°C and it takes about 2 to 5 hours for completion of reaction.

The process of the present invention provides pure 2-chloro-./V-(2,6-dimethylphenyl) acetamide which does not require any further purification. The advantage of above reaction realized in the reduction of the formation of impurities due to mild reaction conditions, which eliminates acid treatment and costly and time consuming purification steps. Additionally, the present invention avoids the use of organic solvents during this reaction which makes the process inexpensive and environment friendly for industrial scale production.
2-Chloro-J/V-(2,6-dimethylphenyl) acetamide of formula III obtained above is converted to jV-(2,6-dimethyl phenyl)-l-piperazine acetamide of formula IV

(Figure Remove)

Formula IV
by reacting with piperazine in alcoholic solvents.
Particularly, the above chloro compound of formula III along with piperazine is taken in alcoholic solvents such as ethanol, methanol, isopropanol and the like and the reaction mass is heated for few hours at reflux temperature. After completion of the reaction, which is monitored by thin layer chromatography, the reaction mass is cooled to ambient temperature and optionally charcolized. The reaction mass is diluted with demineralized water and further cooled to a temperature of below 25°C and preferably below 15 °C to precipitate dimer impurity of formula VI.
CH3
(Figure Remove)

The dimer impurity is filtered off through hyflo bed and the filtrate is extracted with halogenated solvents such as methylene dichloride. The organic layer obtained is washed with aqueous sodium hydroxide solution. Organic layer is washed again with demineralized water and the solvent may be removed using techniques commonly known to one skilled in the art. The solvent is preferably removed by distillation from the reaction mixture by vacuum or atmospheric pressure to obtain pure N-(2,6-dimethyl phenyl)-l-piperazine acetamide of formula IV in high yield.
Yet another embodiment of the present invention provides a process for the preparation of ranolazine of formula I by the condensation of 1 -methoxy-2-(oxiranyl methoxy) benzene of formula II and jV-(2,6-dimethyl phenyl)-l-piperazine acetamide of formula IV in an inert solvent at reflux temperature.
The solvent may be selected from alcohols or aromatic hydrocarbons, such as methanol, ethanol, isopropanol and the like or toluene, xylene and the like and preferably toluene is used. The progress of reaction is monitored by high performance liquid chromatography. After completion of reaction, the reaction mixture is cooled to ambient temperature and given an acid base treatment to remove unreacted starting compounds. To the reaction mass dilute hydrochloric acid is added and layers are separated after stirring. The aqueous layer so obtained is washed preferably with same solvent and is neutralized using suitable base till pH is adjusted to 7-8. Typical bases include, but are not limited to, inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like and preferably sodium bicarbonate is used. After neutralization of aqueous solution, the product is extracted in organic solvent. The organic solvent may be one or more of a chlorinated solvent, or mixtures thereof. The chlorinated solvent may include one or more of dichloromethane, dichloroethane, and chloroform. The solvent is distilled out to

obtain ranolazine, which can optionally be further recrystallized to obtain highly pure ranolazine.
In yet another embodiment, the present invention provides a process for the purification of crude ranolazine by recrystallization with suitable organic solvent such as alcohols or aromatic hydrocarbons to obtain highly pure ranolazine having purity greater than 99%.
In the detailed embodiment of the present invention, crude ranolazine is taken in a suitable organic solvent selected from alcohols or aromatic hydrocarbons. The solvent may include one or more of C\-C$ alcohols, toluene, and the like. The solution so formed is heated to reflux till a clear solution is obtained. Thereafter 10-15% of the solvent is distilled out at atmospheric pressure and the reaction mass is cooled to a temperature of 15-40°C and stirred for 2-5 hours. Further the reaction mass is cooled to a temperature of below 15°C and stirred for few hours. The solid mass so formed is filtered and washed with the same solvent to form highly pure ranolazine having purity greater than 99.5%.
Pharmaceutical ly acceptable salts like dihydrochloride can be prepared by standard techniques known in the prior art. According to yet another embodiment of the present invention, the free base form of ranolazine is dissolved in a suitable solvent, such as ethanol, toluene. Typically, ranolazine in ethanol is reacted with excess of concentrated hydrochloric acid at ambient temperature. The reaction mass is maintained at reflux temperature for a time sufficient to complete the reaction. The reaction temperature is preferably maintained at about 80°C. The clear solution so obtained is charcolized and stirred further for a period of about half an hour at the reflux temperature.

Ranolazine dihydrochloride can thus be isolated by the methods known in the prior art and well known to the person skilled in art including filtration. The filtered mass may then be cooled. Preferably, the reaction mixture is cooled to a temperature of below 10°C with continuous stirring. The precipitate is then preferably collected by filtration and washed with an appropriate solvent to afford ranolazine dihydrochloride.
The present invention will now be illustrated by the following examples, which are not intended to limit the effective scope of the claims. Consequently, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as claimed. The present invention has been described in terms of its specific embodiments and various modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of present invention.
EXAMPLES
Example 1
Step 1: Preparation of l-methoxy-2-(oxiranvI methoxy)benzene
To the cooled solution of sodium hydroxide (40 g in 200 ml demineralized water) a solution to 2-methoxyphenol (100 g), toluene (800ml), and tetra butylammonium bromide (20 g) was added. The reaction mixture was stirred for 30 minutes at 25-30°C. To this, epichlorohydrin (100 g) was added slowly. The reaction mass was stirred for 6 hours at 35-40°C. After completion of reaction (monitored by TLC), layers were separated and aqueous layer was extracted twice with toluene. The toluene layer was first washed successively with water and sodium chloride solution and thereafter charcoalized. The solvent was distilled out to get the title compound as oil (88 g), having purity of 84.21% and dimer impurity of 7.59%.

High vacuum distillation of the above oil at 130-150°C (5 bar) afforded 58 g of the title compound having purity of 96.10% and dimer impurity is not detected by high performance liquid chromatography.
Step 2: Preparation of 2-chloro-7V-(2,6-dimethylphenyl)acetamide
2,6-Dimethylaniline (100 g) was added to a solution of sodium bicarbonate (91 g in 1.0 / water) and reaction mass was cooled to 0 to -5°C. To the reaction mass, chloroacetyl chloride (106 g) was added slowly at 0 to -5°C. The reaction mass was stirred for 3 hours at 0 to -5°C. After completion of reaction (monitored by thin layer chromatography), the solid obtained was filtered and washed with demineralized water to afford 142 g of the title compound having purity 98.97% by high performance liquid chromatography. Yield-87%
Step 3: Preparation of ./V-f2,6-dimethyl phenylM-piperazine acetamide
2-Chloro-/V-(2,6-dimethylphenyl) acetamide (100 g) and piperazine (182 g) was taken in ethanol (300 ml) and the reaction mass was refluxed for 3 hours at 80°C. The reaction completion was monitored on thin layer chromatography. After reaction completion, the reaction mass was cooled to 25-30°C and demineralized water (800 ml). The reaction mass was cooled to 5-10°C and stirred for 30 minutes. The reaction
mass was filtered through hyflo bed and washed with demineralized water (200 ml).
< Reaction mass was extracted with methylene dichloride and organic layer so obtained
was washed with sodium hydroxide solution (20 g sodium hydroxide in 340 ml demineralized water). Organic layer was washed again with demineralized water (100 ml) and then with sodium chloride solution. The solvent was distilled out under vacuum and n-hexane (300 ml) was added to the oil obtained and stirred at room temperature for 5 hours. The solid so obtained was filtered and washed with n-hexane

(100 ml) at ambient temperature to afford 96 g of the title compound having purity 99.08 % by high performance liquid chromatography. Yield- 77%
Step 4; Preparation of Ranolazine
AH^-dimetbyl phenyl)-l-piperazine acetamide (50 g), l-methoxy-2-(oxiranyl methoxy) benzene (40 g) and toluene (400 ml) was refluxed for 5 hours at 120°C. The reaction was monitored was done by high performance liquid chromatography. The reaction mixture was cooled to 25-30°C and dilute hydrochloric acid (70 nil cone, hydrochloric acid in 500 ml demineralized water) was added to the reaction mass. Aqueous layer obtained was washed with toluene and sodium bicarbonate was added to it in lots till a pH of 7-8 was obtained, followed by the addition of methylene chloride. The reaction mass was extracted with methylene dichloride, the solvent was distilled out under reduced pressure. Crude ranolazine was taken in ethanol (300 ml) and heated to reflux at 80°C till clear solution. The solvent (50 ml) was distilled out at atmospheric pressure. The reaction mass was cooled to 20-30°C and stirred for 2 hours. Further reaction mass was cooled to 5-10°C and stirred for 2 hours at 5-10°C. The solid thus obtained was filtered, washed with ethanol (50 ml) and dried at 50-60 °C to afford 70 g of the title compound having purity 99.58% by high performance liquid chromatography,
Step 5: Preparation of Ranolazine Dihydrochloridc
Concentrated hydrochloric acid (23 ml) was added to ranolazine (50 g) in ethanol (500 ml) at 25-30°C and reaction mass was heated for 30 minutes at reflux temperature and charcolized. The filtrate was cooled to 5-10 °C. The solid thus obtained, was filtered, and washed with chilled ethanol (50 ml) to obtain 54 g of the title compound having purity 99.80 % by high performance liquid chromatography. Yield-92%

Example 2
Step 1: Preparation of l-methoxy-2-(oxiranvl methoxy)benzene
To the cooled solution of sodium hydroxide (40 g in 200 ml demineralized water) a solution to 2-methoxyphenol (100 g), toluene (800ml), and tetra butylammonium bromide (20 g) was added. The reaction mixture was stirred for 30 minutes at 25-30°C. To this, epichlorohydrin (100 g) was added slowly. The reaction mass was stirred for 6 hours at 35-40°C. The completion of reaction was monitored by thin layer chromatography. After reaction completion, the reaction mass was extracted twice with toluene and organic layer obtained was washed with water and then with sodium chloride solution. Thereafter organic layer was charcoalized, and the solvent was distilled out to get the title compound as oil (88 g), having purity 84.21% and dimer impurity 8.28%.
High vacuum distillation of the above oil at 130-150°C (5 bar) afforded 60 g of the title compound as pure oil having purity 92.84 % and dimer impurity 0.54 % by high performance liquid chromatography.
Step 2: Preparation of l-chloro-A^Z^-dimethvlphenvDacetamidc
2,6-Dimethylaniline (100 g) was added to a solution of sodium bicarbonate (91 g in 1.0 / water) and reaction mass was cooled to 0 to -5°C. To the reaction mass, chloroacetyl chloride (106 g) was added slowly at 0 to -5°C. The reaction mass was stirred for 3 hours at 0 to -5°C. After reaction completion (monitored by thin layer chromatography), the solid obtained was filtered and washed with demineralized water to afford 135 g of the title compound having purity 98.72% by high performance liquid chromatography. Yield-82%

Step 3: Preparation of ./V-(2,6-dimethyl phcnyD-l-pinerazine acetamide
2-Chloro-jV-(2,6-dimethylphenyl) acetamide (125 g) and piperazine (223 g) was taken in ethanol (325 ml) and the reaction mass was refluxed for 3 hours at 80°C. The reaction completion was monitored on thin layer chromatography. After reaction completion, the reaction mass was cooled to 25-30°C and demineralized water (1.0 /). The reaction mass was cooled to 5-10°C and stirred for 30 minutes. The reaction mass was filtered through hyflo bed and washed with demineralized water (250 ml). Reaction mass was extracted with methylene dichloride and organic layer so obtained was washed with sodium hydroxide solution (25 g sodium hydroxide in 425 ml demineralized water). Organic layer was washed again with demineralized water (125 ml) and then with sodium chloride solution. The solvent was distilled out under vacuum and n-hexane (500 ml) was added to the oil obtained and stirred at room temperature for 5 hours. The solid so obtained was filtered and washed with n-hexane (125 ml) at ambient temperature to afford 123 g of the title compound having purity 98.31 % by high performance liquid chromatography. Yield- 78%
Step 4: Preparation of Ranolazinc
Af-(2,6-dimethyl phenyl)-!-piperazine acetamide (125 g), l-methoxy-2-(oxiranyl methoxy) benzene (100 g) and toluene (1 /) was refluxed for 5 hours at 120°C. The reaction was monitored was done by high performance liquid chromatography. The reaction mixture was cooled to 25-30°C and dilute hydrochloric acid (175 ml cone, hydrochloric acid in 1.25 / demineralized water) was added to the reaction mass. Aqueous layer obtained was washed with toluene (250 ml) and sodium bicarbonate was added to it in lots till a pH of 7-8 was obtained, followed by the addition of methylene chloride. The reaction mass was extracted with methylene dichloride, the solvent was distilled out under reduced pressure.

Purification of Ranolazine
Crude ranolazine obtained above was taken in ethanol (750 ml) was and heated to reflux at 80°C. Clarity of the solution was checked. The solvent (125 ml) was distilled out at atmospheric pressure. The reaction mass was cooled to 20-3 0°C and stirred for 2 hours. Further reaction mass was cooled to 5-10°C and stirred for 2 hours at 5-10°C. The solid was filtered and washed with ethanol (125 ml) to afford 175 g of the title compound having purity 99.49% by high performance liquid chromatography.
Step 5: Preparation of Ranolazine Dihydrochloridc
Concentrated hydrochloric acid (55 ml) was added to ranolazine (100 g) in ethanol (1000 ml) at 25-30°C and reaction mass was heated for 30 minutes at reflux temperature and charcolized. The filtrate was cooled to 5-10 °C. The solid thus obtained, was filtered, and washed with chilled ethanol (100 ml) to obtain 108 g of the title compound having purity of 99.64 % by high performance liquid chromatography. Yield - 92%

WE CLAIM
1. A process for the preparation of pure l-[3-(2-methoxyphenoxy)-2-hydroxy propyl] -4- [(2,6-dimethylphenyl) amino carbonylmethyl] piperazine (Ranolazine) of formula I, and its salts,
(Figure Remove)

Formula I
which comprises:
a) reacting 2-methoxyphenol with epichlorohydrin in the presence of base in a
suitable organic solvent, using phase transfer catalyst to afford l-methoxy-2-
(oxiranyl methoxy)benzene of formula II,

(Figure Remove)

Formula II
b) reacting 2,6-dimethylaniline with chloroacetyl chloride in presence of base in water to afford 2-chloro-./V-(2,6-dimethylphenyl)acetamide of formula III,

H
Formula III
c) reacting 2-chloro-A7-(2,6-dimethylphenyl)acetamide of formula III with piperazine in ethanol to form Af-(2,6-dimethyl phenyl)-l-piperazine acetamide of formula IV,

(Figure Remove)

Formula IV
d) condensing jV-(2,6-dimethyl phenyl)-!-piperazine acetamide of formula IV
with 1 -methoxy-2-(oxiranyl methoxy)benzene of formula II in an inert
solvent to form ranolazine,
e) converting ranolazine to its pharmaceutically acceptable salts by treating with
mineral acid by conventional methods.

2. A process according to claim 1, wherein in step a, solvent is toluene, base is
sodium hydroxide and phase transfer catalyst is tetrabutylammonium bromide.
3. A process according to claim 1, wherein in step b, base is sodium bicarbonate.
4. A process according to claim 1, wherein in step d, the inert solvent is selected
from alcohols and aromatic hydrocarbons and preferably toluene is used.

5. A process for the preparation of 1 -methoxy-2-(oxiranyl methoxy) benzene of formula II,
Q

(Figure Remove)

Formula II
which comprises reacting 2-methoxyphenol with epichlorohydrin in an organic solvent in the presence of a phase transfer catalyst and base.
6. A process according to claim 5 wherein the organic solvent is selected from and
one or more of hydrocarbon, chlorinated solvent such as toluene, xylene,
dichloromethane, dichloroethane, and chloroform or mixtures thereof.
7. A process according to claim 5 wherein the phase transfer catalyst is selected
from quaternary ammonium compounds and phosphonium compounds preferably
tetrabutylammonium bromide.
8. A process for the preparation of 2-chloro-A^-(2,6-dimethylphenyl)acetamide of formula III,
(Figure Remove)

Formula III
which comprises reacting 2,6-dimethyl aniline with chloroacetyl chloride in presence of a suitable base in water.

9. A process according to claim 8 wherein the base is selected from sodium
hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium
bicarbonate, potassium carbonate, potassium bicarbonate and preferably sodium
bicarbonate is used.
10. A process for the purification of ranolazine, comprises, dissolving crude
ranolazine in a solvent selected from alcohols or aromatic hydrocarbons at reflux
temperature, cooling the reaction mass and isolating the pure ranolazine by
filtration.
Dated this day 17th of October, 2006

Dr. Asha Aggarwal
HEAD-IPR
Ind-Swift Laboratories Limited