FORM - 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION (See section 10; rule 13)
"A PROCESS FOR THE PREPARATION OF -RANOLAZINE & ITS INTERMEDIATES THEREOF"


Aarti Healthcare Limited
An Indian Company
Registered under Indian Companies Act 1956,
Having its registered Office at
71, Udhyog Kshetra, 2nd Floor,
Mulund-Goregaon link Road,
Mulund (West), Mumbai- 400080,
Maharashtra, India.

The following specification particularly describes the invention and the manner in which it is to be performed:


FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Ranolazine and pharmaceutically acceptable salts thereof. More particularly it relates to an improved process to prepare highly pure Ranolazine and intermediates useful in the preparation of Ranolazine.
BACKGROUND OF THE INVENTION
The formula-A represents Ranolazine which chemically is also known as N-(2, 6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy) propyl]-1 -Piperazine-acetamide.

(A)
Ranolazine is a popular anti-anginal and anti-ischemic agent and thus finds a large application in the pharmaceutical industry.
In prior art, US 4567264, the patent document discloses two processes for the preparation of Ranolazine. One of these processes is referred herein. Please refer to Fig.l. Thus one of the processes of US 4567264 (hereinafter referred as "Scheme-1"), 2, 6-dimethylaniline derivative of formula (iv) is reacted with chloroacetyl chloride (v) in the presence of triethyl amine in methylene dichloride solvent to give an amide intermediate (vi) which is further reacted with piperazine (1) to form piperazine derivative (viii). The piperazine derivative (viii) thus obtained is further reacted with an appropriate oxirane derivative (iii) (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 to obtain Ranolazine (A) which is isolated as an oil using column chromatography. Ranolazine (A) obtained in the previous step, is converted to its dihydrochloride acid salt using excess of Hydrochloric acid.

The above process suffers from some inherent drawbacks:
a. The product obtained is dark brown in color and requires further purification
which results in more consumption of solvents for purification purposes. This also
amounts to a loss in yield.
b. During the preparation of oxirane derivative (iii), impurity 1, 3-bis-(2-
methoxyphenoxy)-propan-2-ol of formula (X)

is also formed in a percentage of 20-30% which can not be removed easily. This
amounts to a loss in yield of the oxirane derivative that directly results in a loss in
yield of the final product thus making the process non-viable for industrial scale
production.
c. During condensation of piperazine derivative (viii) with oxirane derivative (iii),
mixture of solvents is used and further column chromatography is adopted for the
isolation of Ranolazine. The isolation technique is complex, time consuming,

expensive and inconvenient as it requires a large volume of solvent and more time to obtain the product. Thus the process to obtain the product on a large scale fails.
In another prior art, WO 2008/047388, it also discloses a process for the preparation of Ranolazine. The patent document also discloses a process for the preparation of l-(methoxy-2-(oxiranylmethoxy)-benzene (iii) and a reaction of amide derivative with piperazine.
This prior art method/process has following disadvantages:
a. The preparation of l-(methoxy-2-(oxiranylmethoxy)-benzene (iii) is carried out in
a biphasic solvent system in the presence of phase transfer catalyst. The work up is
lengthy and tedious. The organic layer is charcoalized to give 84% purity with the
dimer impurity of
7.59% which further requires the product to be distilled out under high vacuum to give the product with purity of 96%. There is considerable loss of yield during high vacuum distillation from 88 gms to 56 gms and thus the process is industrially unacceptable. The purity which is 96% also amounts to a loss in the yield in the final product.
b. It is also observed that at the time of the reaction of piperazine with amide
derivative generates dimmer impurity of formula (Y) which can not be easily
removed.

Further purification is required to remove the said dimmer impurity (Y) which directly affects the yield and purity of the final product of formula (A).
So, in view of the above disadvantages, it is clear that the prior art processes for the preparation of Ranolazine involve stringent reaction conditions and use of column chromatography which is unsuitable for large scale production. Further the removal of significant amount of unwanted impurities formed during the reaction requires multiple steps of purification that results into the low yield of the final product i.e. Ranolazine of formula (A).

Hence, a simple and cost effective process to prepare Ranolazine, which is easy to implement on industrial scale, is the urgent need of the hour.
It is therefore, an object of the present invention to provide an efficient and industrially viable process for preparing Ranolazine and its salts in high yield and high purity thereby eliminating tedious and complex processes like column chromatography and multiple purification steps.
OBJECTS OF THE PRESENT INVENTION:
The major object of the present invention is to provide a simple and cost effective process to prepare pure Ranolazine of formula (A) and its pharmaceutically acceptable salts.
It is also an object to provide an improved process for the preparation of Ranolazine with high yield and high purity which comprises:
a) reacting 2-methoxyphenol (i) with a predetermined amount of
epichlorohydrin (ii) in presence of aqueous base and a phase transfer catalyst
and in absence of organic solvent to give l-methoxy-2-
(oxiranylmethoxy)benzene of formula (iii)

b) reacting 2, 6-dimethyl aniline (iv) with chloroacetyl choride (v) in an
aromatic solvent in presence of organic base between at -5 to 5°C to afford 2-
chloro-N-(2,6-dimethylphenyl)acetamide of formula (vi).


c) reacting 2-chloro-N-2,6-dimethylphenyl) acetamide (vi) with piperazine monohydrochloride (vii) in alcoholic solvent to obtain N-(2,6-dimethylphenyl)-!-piperazine acetamide of formula (viii).

d) reacting N-(2,6-dimethylphenyl)-l-piperazine acetamide of formula (viii) with l-methoxy-2-(oxiranylmethoxy)benzene of formula (iii) in ketonic solvent to give crude Ranolazine of formula (A).

e) Purifying crude Ranolazine (A) in ketonic solvent at reflux temperature to give pure Ranolazine of formula (A).
It is yet another object of the present invention to provide a process for the preparation of l-methoxy-2-(oxiranylmethoxy)benzene of formula (iii) with high yield and purity which comprises reacting 2-methoxyphenol (i) with an excess predetermined amount of epichlorohydrin (ii) in presence of aqueous base and a phase transfer catalyst in absence of solvent.
It is also an object of the present invention to provide a process for the preparation of N-(2, 6-dimethylphenyl)-l-piperazine acetamide of formula (viii) with high yield

and purity which comprises reacting 2-chloro-N-(2,6-dimethylphenyl)acetamide of formula (vi) with piperazine monohydrochloride (vii) in alcoholic solvent.
It is also an object of the present invention to provide a process for the preparation of Ranolazine of formula (A) with high yield and purity which comprises:
a) reacting 2-chloro-N-(2,6-dimethylphenyl)acetamide of formula (vi) with piperazine monohydrochloride (vii) in alcoholic solvent to obtain N-(2,6-dimethylphenyl)-l -piperazine acetamide of formula (viii).
b) reacting N-(2,6-dimethylphenyl)-l-piperazine acetamide of formula (viii) with 1- methoxy-2-(oxiranylmethoxy)benzene (iii) in ketonic solvent to give Ranolazine of formula (A).
If desired, Ranolazine of formula (A) can be converted in to its pharmaceutically acceptable salts using conventional methods.
DETAILED DESCRIPTION OF THE PRESENT INVETION:
The present invention relates to the process for the preparation of Ranolazine of formula (A) and its pharmaceutical acceptable salts. More particularly, the present invention relates to the process for the preparation of Ranolazine intermediates i.e. l-methoxy-2-(oxiranylmethoxy)benzene of formula (iii) and N-(2, 6-dimethylphenyl)-l -piperazine acetamide of formula (viii) with a high yield and purity. The present invention also discloses the process for the preparation of Ranolazine of formula (A) using these intermediates.
One of the embodiments of the present invention provides a process for the preparation of l-methoxy-2-(oxiranylmethoxy)benzene of formula (iii) with high yield and purity.
According to the embodiment, in absence of an organic solvent, 2-methoxy phenol (i) is reacted with a predetermined amount of epichlorohydrin (ii) in presence of aqueous base and phase transfer catalyst to give l-methoxy-2-(oxiranylmethoxy)benzene of formula (iii).

It has been observed that l-methoxy-2-(oxiranylmethoxy)benzene of formula (Hi) which is prepared by the prior art processes also contains 5-20% impurity of the formula (X)
which further needs purification of the product which ultimately results the low yield and lengthy process not suitable for industrial production.
Surprisingly, it has been found that use of excess epichlorohydrin helps to reduce the impurity formation during the reaction. The yield of the highly pure product is also increased by this process. Table-1 shows the comparison of the present invention with the prior art processes which was carried out in house. It also found that the use of excess epichlorohydrin helps to complete the reaction in a lesser time to give a pure product with a greater yield and purity as compared to the prior art process.
Epichlorohydrin (ii) in the reaction can be taken in an amount of 3 to 6:1 mole equivalent compared to 2-methoxy phenol (i). Epichlorohydrin acts as a solvent and a reactant in the reaction and so no other organic solvent is required for the reaction. It is also observed that the use of excess epichlorohydrin in the above ratio improves the yield and purity of the product and gives more than 80% yield along with more than 98% purity of the product of formula (iii) which is not obtainable with the use of organic solvent in the reaction. Epichlorohydrin can be recovered after the completion of the reaction and for the same reaction. It is preferred to use phase transfer catalyst to accelerate the rate of the reaction.
This can be well explained with the following table-1 without any limitation.
Table-1

Experiment No. Reactants in Mole Ratio 2-OMe Phenol: Epichlorohydrin & Organic Solvent Aq. Base, PTC Reaction conditions Yield and Purity (After distillation)
RD/Zen 1/0901/088 1:2 NaOH,
2.5% 3 hrs, 40-45°c 64%; 97% by GC
RD/Zen 1/0901/271 1:10 & NaOH 6 hrs, 70-75uc 65%; 97.5% by TLC

Toluene-10V to Phenol 2.5%
RD/Zen 1/0901/285 1:4&
Toluene-5V to Phenol NaOH
2.5% 3 hrs, 90uc 69%; 97% by GC
RD/Zen 1/0901/287 1:4 NaOH
2.5% 3 hrs, 40-45uc 81%;98%by GC
RD/Zen 1/0901/290 1:2&
Toluene-2V to Phenol NaOH
2.5% 14 hrs,40-45°c 32%; 50% by TLC Reaction not completed
RD/Zen 1/0902/01 1:3 NaOH
2.5% 3 hrs, 40-45uc 84%; 98% by GC
RD/Zen 1/0902/02 1:3 NaOH
2.5% 3 hrs, 40-45uc 82.2%; 98.3% by GC
RD/Zen 1/0902/03 1:3 NaOH
2.5% 3 hrs, 40-45°c 84%; 98% by GC
The inorganic bases reported in the prior art can be used for the reaction.
At least one Phase transfer catalyst (PTC) can be used in the amount of 2-3% compared to the quantity of 2-methoxy phenol. Phase transfer catalyst can be selected from the class of quaternary ammonium compounds, quaternary phosphonium compounds which may cover but not limited to, tetrabutylammonium bromide, tetrabutylammonium hydroxide, tetrabutyl ammonium hydrogen sulfate, triethylbenzylammonium chloride.
Generally the reaction mass is stirred for 2-6 hrs at between 25-50°C, more preferably between at 40-50°C. After completion of the reaction, two layers are separated and the organic layer of epichlorohydrin containing the product is taken for distillation to give pure product along with more than 98% purity and more than 80% yield.
The dimer impurity of formula (X) namely, 1, 3-bis-(2-methoxy-phenoxy)-propan-2-ol is almost absent or in negligible quantity in the desire product.

(X)
Another embodiment of the present invention is to provide a process for the preparation of 2-chloro-N-(2,6-dimethylphenyl)acetamide of formula (vi). According to the present invention 2,6-dimethyl aniline (iv) is reacted with

chloroacetyl choride (v) in an aromatic solvent in presence organic base between at -5°C to 5°C to afford 2-chloro-N-(2,6-dimethylphenyl)acetamide of formula (vi).
The aromatic solvent is selected from the inert solvents but not limited to, toluene, xylene in a quantity of 2-10 volumes compared to 2,6-dimethyl aniline. The organic base used in the reaction is selected but not limited to, triethyl amine, tributyl amine in a molar ratio of 1-1.5:1 with compared to 2, 6-dimethyl aniline.
The reaction is carried out between at -5°C to 5°C, more preferably 0 to 5°C. After completion of the reaction, water is added to the reaction mass and the mass filtered followed by washing the wet cake with aqueous sodium bicarbonate solution to give 2-chloro-N-(2,6-dimethylphenyl)acetamide of formula (vi).
The process of the present invention provides pure 2-chloro-N-(2,6-dimethylphenyl)acetamide of formula (vi) which can be taken for the next step without any purification. The advantage of the present invention is that the aromatic solvent used in the reaction can be recovered and reused. Additionally, it avoids the use of the water miscible solvents which can not recovered.
Yet another embodiment of the present invention is to provide a process for the preparation of N-(2,6-dimethylphenyl)-l-piperazine acetamide of formula (viii). According to the present invention, 2-chIoro-N-(2,6-dimethylphenyl)acetamide of formula (vi) is reacted with piperazine monohydrochloride (vii) in alcoholic solvent to obtain N-(2,6-dimethylphenyl)-l-piperazine acetamide of formula (viii). The advantage for the use of piperazine monohydrochloride in place of piperazine in the reaction is that hydrochloride salt of piperazine does not allow the formation of the dimer impurity of formula (Y) during the reaction which results in a product with more than

99.2% HPLC purity and more than 85% of yield with out any purification of the product.

Piperazine monohydrochloride may be used in the quantity of 2-4 mole equivalent compared to the 2-chloro-N-(2, 6-dimethylphenyl)acetamide. Piperazine monohydrochloride (vii) can be prepared from piperazine hexahydrate and piperazine dihydrochloride.
According to the present invention, piperazine hexahydrate is reacted with piperazine dihydrochloride in an alcoholic solvent to give piperazine monohydrochloride (vii). In the said reaction mass, 2-chloro-N-(2, 6-dimethylphenyl)acetamide (vi) is added. The reaction is stirred for 3-8 hrs at a temperature between 30°C to the reflux temperature of the selected alcoholic solvent, preferably between at 30-70°C, more preferably between 55-70°C. The alcoholic solvent for the reaction is selected from methanol, ethanol, isopropanol, butanol.
After completion of the reaction, solvent is removed under vacuum and diluted acetic acid is added in the reaction mass. The reaction mass is then extracted with an immiscible organic solvent like dichloromethane. The aqueous layer is separated out and adjusted pH=l 1-12 using an aqueous alkali solution. The concentration of the aqueous base is between 30-50%, more preferably 40-50% in water. The reaction mass is then extracted with dichloromethane (MDC). The MDC layers is then taken for distillation and MDC is removed completely from the reaction mass followed by addition of ether solvent like but not limited to, diisopropyl ether (DIPE). The base used in the work up is selected from the inorganic bases but not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH).
The product which is obtained by the above process is having HPLC purity of more than 99.2%. The yield of the product is in excess of 85%.
Another embodiment of the present invention is to provide a process for the preparation of Ranolazine of formula (A). According to the present invention, 1-methoxy-2-(oxiranylmethoxy)benzene of formula (iii) is reacted with N-(2,6-dimethylphenyl)-l -piperazine acetamide (viii) in a ketonic solvent at a temperature between 50 C to reflux temperature of the ketonic solvent used in the reaction.
It is observed that the ketonic solvent which is used for the reaction also helps to remove impurities unlike the other solvents used in the reaction. The advantage of

the use of the ketonic solvent is that it avoids a lengthy work up like acid-base extraction. Additionally, ketonic solvent also reduces the impurity formed in the reaction and also can be recovered which makes the process environmental friendly, cost efficient and suitable for industrial production. The ketonic solvent may be selected from but not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone in the quantity of 5 to 12 volumes compared to l-methoxy-2-(oxiranylmethoxy)benzene (iii). After completion of the reaction, optional charcoal treatment is given to the mass at reflux temperature of a ketonic solvent. Solvent is removed from the mass completely and again fresh ketonic solvent is added in the mass. The reaction mass is then cooled to 0 to 5°C and the product filtered to give the wet cake. The wet cake is washed with ketonic solvent followed by drying in the oven to give pure Ranolazine of formula (A). Ranolazine obtained from the reaction is highly pure which is having HPLC purity of more than 99.7% along with the yield of more than 88%.
The ketonic solvent used in the optional purification is selected from acetone, methyl ethyl ketone or methyl isobutyl ketone in a volume of 5-12 v/w compare to crude Ranolazine (A).
Pharmaceutically acceptable salts of Ranolazine like Ranolazine dihydrochloride can be prepared by the standard processes known in the prior art.
The present invention is now illustrated by the following examples, which are not intended to limit the scope of the invention. The present invention has bee 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 the present invention.
i
EXAMPLES:
1. Preparation of l-methoxy-2-(oxiranylmethoxy)benzene (iii):
To a mixture of 2-methoxy phenol (100 gm), epichlorohydrin (300 ml) and tetrabutyl ammonium chloride (2.5 gm), an aqueous NaOH solution (32,2 gm in 32.2 ml water) is added at 40-45°C. The reaction mass is stirred for 3 hrs at 40-45°C. After completion of the reaction (monitored by TLC), mass is cooled to room temperature. The reaction mass is filtered to obtain two clear layers. The organic

layer is separated and washed with water twice. The washed organic layer is taken
for distillation to collect excess epichlorohydrin from the mass at 70°C under
vacuum. After removal of excess epichlorohydrin, the reaction mass is further
distilled at high vacuum at between 140-200CC to collect the product from the
reaction mass.
Product: 1 -Methoxy-2-(oxiranylmethoxy)benzene
Dry weight: 145.2 Gms
Yield: 82% (based on 2-methoxy phenol)
HPLC purity: 98%
2. Preparation of 2-chIoro-N-(2, 6-dimethylphenyI)-acetamide (vi):
In a mixture of toluene (500 ml) and triethyl amine (100 gm), 2, 6-dichloroaniIine (100 gms) is added drop wise under stirring at a temperature between -3°C to 5°C. After completion of the addition of 2,6-dichloro aniline, chloroacetyl chloride (112 gms) is added to the reaction mass under stirring at a temperature between -3°C to 5°C. The reaction mass is stirred at between -5°C to 5°C for 3 hrs. After completion of the reaction (monitored by TLC), 1 litre chilled (0-5°C) demineralized water is added in the reaction mass under stirring. The solid precipitated out is filtered and washed with chilled demineralized water. The product is treated with an aqueous solution of sodium bicarbonate, filtered, washed with water to give wet product which is then dried in an oven at 50°C. Product: 2-Chloro-N-(2,6-dimethylphenyl)-acetamide Dry weight: 147.3 Gms Yield: 90% (based on 2, 6-dichloro aniline)
3. Preparation of N-(2,6-dimethylphenyl)-l-piperazine acetamide (viii):
Piperazine hexahydrate (147.7 gms), methanol (300 ml) is added in a 3 necked RBF. The reaction mass is heated to 65-70°C to get a clear solution. The reaction mass is then cooled to 45-50°C and piperazine dihydrochloride (269 gms) is added to the reaction mass. After stirring half an hour, 2-chloro-N-(2, 6-dimethylphenyl)-acetamide (100 gms) is added in the reaction mass at 40-45°C and stirred the reaction mass at 65-70°c for 6 hrs. After completion of the reaction (monitored by TLC), the reaction mass is cooled to 10-15°C, filtered, and the filtrate washed with methanol. The filtrate is collected and taken for distillation under vacuum at 40-45°C

to remove methanol from the mass. After removal of methanol, 15% aqueous acetic
acid (600 ml) is added, the mass stirred and filtered to get clear solution. To the
solution, dichloro methane (MDC) is added and separated the aqueous layer. In the
obtained aqueous layer, aqueous NaOH solution (100 gm NaOH is dissolved in 200
ml water) is added at 10-15°C to adjust pH to about 11.0.
The reaction mass is then extracted with MDC thrice. MDC layer is collected
together and MDC removed completely from the mass. DIPE (300 ml) is added to
the residue and the whole stirred at 0-5°C for 2 hrs. The slurry is filtered, washed
with DIPE followed by drying in oven at 50°C to give the desired product.
Product: N-(2,6-dimethylphenyl)-l-piperazine acetamide
Dry weight: 113.8 Gms
Yield: 91% (based on 2-chloro-N-(2, 6-dimethylphenyl)-acetamide)
HPLC purity: 99.23%
4. Preparation of pure Ranolazine (A):
N-(2,6-dimethylphenyl)-l-piperazine acetamide (50 gms) and acetone are charged in
to a 3 necked RBF. l-Methoxy-2-(oxiranylmethoxy)benzene (44 gms dissolved in
44 ml acetone} is added to the above solution at reflux temperature within 8-9 hrs
under stirring. The reaction mass is then stirred at reflux temperature for 30 minutes.
After completion of the reaction (monitored by TLC), charcoal (5.0 gms) is added to
the reaction mass and the whole stirred at reflux temperature for 30 minutes. The
mass is then filtered and the filtrate washed with hot acetone (50 ml). Filtrate is
collected and acetone is distilled from the mass completely. To the obtained residue,
fresh acetone (70 ml) is added and the mass stirred for 1 hr at 0-5°C, filtered the
product and washed with chilled acetone (50 ml), dried in oven at 50°C to give pure
Ranolazine.
Product: Ranolazine (Pure)
Dry Weight: 76.2 Gms
Yield: 88.2% (based on N-(2, 6-dimethylphenyl)-l-piperazine acetamide)
HPLC purity: 99.78%

We Claim:
1. A process for the preparation of pure Ranolazine of formula (A) comprising:
Reacting 2, 6-dimethyl aniline (iv) with chloroacetyl choride (v) in an
aromatic solvent in presence of organic base between at -5 to 5°C to give 2-
chloro-N-(2,6-dimethylphenyl) acetamide of formula (vi);
Reacting 2-chloro-N-(2,6-dimethylphenyl)acetamide of formula (vi) with
Piperazine monohydrochloride (vii) in alcoholic solvent to obtain N-(2,6-
dimethylphenyl)-l- piperazine acetamide of formula (viii);
Reacting N-(2,6-dimethylphenyl)-l-piperazine acetamide of formula (viii)
with l-methoxy-2-(oxiranylmethoxy)benzene (iii) in ketonic solvent to
produce crude Ranolazine of formula (A);
Purifying the said crude Ranolazine (A) in ketonic solvent at a reflux
temperature to give pure Ranolazine of formula (A).
2. The process as claimed in claim 1, wherein the aromatic solvent is selected
from a group of toluene and xylene.
3. The process as claimed in claim 1, wherein the organic base is selected from a group of triethyl amine and tributyl amine.
4. The process as claimed in claim 1, wherein the alcoholic solvent is selected from a group of methanol, isopropanol, ethanol and butanol.
5. The process as claimed in claim 1 wherein ketonic solvent is selected from a group of acetone, methyl ethyl ketone and methyl isobutyl ketone.
6. The process as claimed in claim 1, wherein the process for preparation of 1 -methoxy-2-(oxiranylmethoxy)benzene of formula (iii) in absence of organic solvent, further comprising:
Reacting 2-methoxyphenol (i) with a predetermined amount of epichlorohydrin (ii) in presence of an aqueous base and a phase transfer catalyst to give l-methoxy-2- (oxiranylmethoxy)benzene of formula (iii).
7. The process as claimed in claim 6, wherein the predetermined amount of
epichlorohydrin (ii) is 3 to 6:1 mole equivalent compared to 2-methoxy
phenol (i).

8. The process as claimed in claim 6, wherein base is selected from a group of sodium hydroxide and potassium hydroxide.
9. The process as claimed in claim 6, wherein phase transfer catalyst is selected from a group of quaternary ammonium and phosphonium compounds.
10. The process as claimed in claim 1 wherein purity of Ranolazine (A) is at least
99.7%.

(Applicant) |DESAI PARIMAL HASMUKHLAL [Director, Aarti Healthcare Limited)
To,
The Controller of Patents Boudhik Sampada Bhavan, Antop Hill, S.M. Road Mumbai - 400 037