FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
NOVEL INTERMEDIATES OF RANOLAZINE AND PROCESSES FOR THEIR
PREPARATION
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI (WEST), MUMBAI -
400 102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

NOVEL INTERMEDIATES OF RANOLAZINE AND PROCESSES FOR THEIR PREPARATION
TECHNICAL FIELD
The present invention relates to novel intermediates of Ranolazine, processes for the preparation of these novel intermediates and their use in the preparation of Ranolazine (I) and its acid addition salts.
BACKGROUND OF THE INVENTION
Ranolazine of formula (I), chemically known as l-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbamoylmethyl]piperazine, is useful as an antianginal agent. Ranolazine is indicated for the treatment of chronic angina. Ranolazine has been shown to exert antianginal and anti-ischemic effects without reducing heart rate or blood pressure. It does not increase the rate pressure product at maximal exercise levels. Ranolazine is represented by the formula (I) as given below.

Ranolazine was first covered in US 4,567,264 (Kluge Arthur F. et al, 1986) which describes its preparation by condensing l-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine (V) with 1-(2-methoxyphenoxy)-2,3-epoxypropane (III). Ranolazine obtained is purified by column

chromatography and isolated as a white powder. The process for preparation of Ranolazine is

EP 0483932 (Agai-Csongor, Eva Rozalia et al, 1992) describes the preparation of Ranolazine by condensation of α-{N,N - bis (2-chloro ethyl) - amino]- 2,6-dimethyl acetanilide with 1 - [ 3 - ( 2 - methoxyphenoxy ) - 2 -hydroxy] propylamine as given in scheme-II. The crude Ranolazine is further purified by column chromatography and is isolated as oil.

WO 2008/139492 (Kompella, Amala kishan et al, 2008) discloses the process for the preparation of Ranolazine by condensation of N-(2,6-dimethylphenyl)-l-piperazineacetamide with l-(2-methoxyphenoxy)-2,3-epoxypropane. It further discloses a purification method that involves

preparation of fumarate salt of Ranolazine by reacting Ranolazine with fumaric acid, which undergoes crystallization followed by neutralization to give pure Ranolazine.
WO 2008/047388 (Saxena, Rahul et al, 2008) discloses the purification methods for Ranolazine by recrystallising Ranolazine base from alcohols such as ethanol or aromatic hydrocarbons, such as toluene. The purity of pure Ranolazine obtained by crystallization is 99.49%.
WO2010/097805 (Siyan, Rajinder Singh et al, 2010) discloses the use of a ketonic solvent or a mixture of ketonic solvent and other organic solvent to purify Ranolazine base.
As described above the cited literature process suffers from many drawbacks like use of excess amount of piperazine during the reaction, which is difficult to handle in large scale; generation of large amount of effluent due to excessive use of piperazine, which is difficult to recover and recycle; Ranolazine obtained as oil is difficult to handle in large scale production and laborious chromatographic techniques are used for purification of Ranolazine.
It is observed that pharmaceutically acceptable salts of Ranolazine when prepared from impure Ranolazine do not meet the pharmaceutical acceptable quality. There is therefore, an unfulfilled need to provide industrially feasible process for the preparation of Ranolazine free base and its acid salts with high purity. The present invention is directed towards the same and provides Ranolazine of high purity by using mono-protected derivative of piperazine, as an intermediate, to prepare Ranolazine.
OBJECT OF THE INVENTION

The main object of the present invention is to provide novel intermediates for the preparation of Ranolazine and its acid addition salt in good to excellent yields.
Further object of the present invention is to provide novel processes for the preparation of the intermediates which subsequently provides Ranolazine and its acid addition salt
Further important objectives of the present invention is to inhibit the formation of a dimer impurity by using protected piperazine derivative.
Yet another object of the present invention is to provide a process for the preparation of Ranolazine by using quantitative amount of piperazine derivative.
Yet another object of the present invention is to provide an economical, environment friendly and operationally simple process of preparing Ranolazine.
SUMMARY OF THE INVENTION
The present invention relates to a novel intermediate of formula (IV)


In another aspect of the present invention, there is also provided a novel intermediate of formula (VI)

wherein Rl is an alkyl or aryl group.
In another aspect of the present invention, there is provided a process for the preparation of novei
intermediate of formula (IV)

wherein R is alkyl or aryl;
comprising reacting [(2,6-Dimethylphenyl)-amino carbonyl methyl] chloride of formula (II)

with N-Carbethoxy piperazine


in presence of an organic solvent and a base.
According to another aspect of the invention, there is provided a process for the preparation of
another novel intermediate, compound of formula (VI)

wherein Rl is alkyl or aryl group; comprising reacting l-(2-Methoxy phenoxy)-2;3-epoxy propane (III)
with N-Carbethoxy piperazine

(VIII) in presence of an organic solvent.

In yet another aspect of the present invention, there is provided an improved process of for the preparation of Ranolazine of formula (I) and its acid addition salts thereof,

which comprises-
a) hydrolysis and concurrent decarboxylation of the carbamate functional group in compound of formula (IV)

wherein R is same as per claim 1; with alkali to give l-[(2,6-dimethylphenyl)amino carbonyl methyl Jpiperazine of formula (V)


a. reacting compound of formula (V) with 1-(2-Methoxy phenoxy)-2,3-epoxy propane of formula (III)
in presence of an organic solvent to give Ranolazine of formula (I)
In yet another aspect of the present invention, there is provided an improved process of for the preparation of Ranolazine of formula (I) and its acid addition salts thereof, comprising

a. hydrolysis and concurrent decarboxylation of the carbamate functional group of compound of formula (VI)

wherein R] same as per claim 1; with alkali to give l-[3-(2-methoxyphenoxy)-2-hydroxypropyfjpiperazine of formula (VII)


^or p'
OH LN^/NH (VII)
b. reacting compound of formula (VII) with [(2)6-dimethylphenyl)-aminocarbonyl methyljchioride of formula (II)

0
JL xi
HN ^-^
H3C\p5^CH3 (")
in presence of an organic solvent and a base to give Ranolazine of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an efficient, industrially advantageous and economical process for the preparation of Ranolazine intermediates and subsequently Ranolazine of formula (I) and its acid addition salts thereof. Further, the process covered in the present invention is very useful and safe, especially related to storage and handling of the reagents during its large scale production of Ranolazine.
The present invention also relates to an improved process for preparing pure Ranolazine having purity > 99.8% by using the novel intermediates. Also the present invention eliminates the use of column chromatography, multiple crystallization processes, and tedious, slow filtration operations, so as to get the final product.

The present invention relates to the process for preparation of Ranolazine and its acid addition salts and is represented under two schemes, Schemes A and B.
In an embodiment of the present invention, Scheme A relates to an improved process for the preparation of novel intermediate, 1-[(2,6-dimethyl phenyl) amino carbonyl methyl]-4-carbethoxy piperazine (IV), wherein 2,6-Dimethyl aniline is reacted with Chloroacetyl chloride in acetone and aqueous base such as potassium carbonate below 5 °C to give [(2,6-DimethyIphenyi)-amino carbonyl methyl]chloride (II), the product is isolated by addition of excess of water. The crude product obtained is used in the next step without purification. Aqueous sodium salt of Guaiacol is reacted with Epichlorohydrin to give l-(2-Methoxy phenoxy)-2,3-epoxy propane (III). This low melting intermediate can be isolated as a pure solid by using a solvent for recrystallisation. The solvent used for recrystallisation is selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol, preferably isopropanol.
The novel intermediate, l-[(2,6-dimethyI phenyl) amino carbonyl methyl]-4-carbethoxy piperazine (IV) is prepared by reacting [(2,6-Dimethylphenyl)-amino carbonyl methyljchloride (II) with N-Carbethoxy piperazine in organic solvent at elevated temperature using a base to give the product. The organic solvent used is selected from xylene, toluene or mixtures thereof, preferably toluene and at reflux reaction temperature. The base is selected from alkali carbonates like lithium carbonate, sodium carbonate, potassium carbonate, preferably sodium carbonate or alkali metal bicarbonates like lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium bicarbonate.

[(2,6-dimethyl phenyl) amino carbonyl methyI]-4-carbethoxy piperazine (IV) in organic solvent on hydrolysis and concurrent decarboxylation of the carbamate functional group with alkali gives l-[(2,6-dimethylphenyl-)amino carbonyl methyl] piperazine (V).
The alkali used is selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably potassium hydroxide. The organic solvent used in hydrolysis is selected from aliphatic alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol, preferably methanol. l-[(2,6-dimethylphenyl-)amino carbonyl methyl] piperazine (V) is reacted with l-(2-Methoxy phenoxy)-2,3-epoxy propane (III) in an organic solvent to give Ranolazine of formula (I). The organic solvent used is selected from polar solvents such as water, acetone, alcohols, preferably aliphatic alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol or mixtures thereof, more preferably isopropanol. The Ranolazine base is further converted to Ranolazine dihydrochloride by recting Ranolazine base with HC1.


Wherein R is alkyl or aryl, and alkyl is selected from methyl, ethyl, propyl or isopropyl, t-butyl, preferably ethyl.
In another embodiment of the present invention, the process of preparation of ranolazine according to Scheme B, relates to preparation of a novel intermediate, l-[3-(2-Methoxy phenoxy)-2-hydroxy propyl]-4-carbethoxy piperazine (VI), wherein 2,6-Dimethyl aniline is reacted with Chloroacetyl chloride in acetone and aqueous base such as potassium carbonate

below 5 °C to give [(2,6-DimethyIphenyl)-amino carbonyl methyljchloride (II), the product is
isolated by addition of excess water. The crude product obtained is used in the next step without
purification.
Aqueous sodium salt of Guaiacol is reacted with Epichlorohydrin to give l-(2-Methoxy
phenoxy)-2,3-epoxy propane (III). This intermediate can be isolated as a pure solid by using
solvent for recrystallisation. The solvent used for recrystallisation is selected from alcohols such
as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol, preferably
isopropanol.
l-(2-Methoxy phenoxy)-2,3-epoxy propane (III) is reacted with N-Carbethoxy piperazine in an
organic solvent to give l-[3-(2-Methoxy phenoxy)-2-hydroxy propyl]-4-carbethoxy piperazine
(VI), which on hydrolysis and concurrent decarboxylation of the carbamate functional group
with alkali gives l-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]piperazine (VII).
The alkali used for hydrolysis is selected from alkali hydroxides such as lithium hydroxide,
sodium hydroxide or potassium hydroxide, preferably potassium hydroxide.
The organic solvent used for preparation of (VI) and its subsequent hydrolysis and
decarboxylation is from aliphatic alcohols such as methanol, ethanol, isopropanol, n-propanol, n-
butanol, isobutanol, tert-butanol, preferably methanol.
1 - [ 3 - ( 2 - Methoxy phenoxy) - 2 - hydroxy propyl ] piperazine (VII) is reacted with [ ( 2, 6 -
Dimethylphenyl)-amino carbonyl methyljchloride (II) in presence of an organic solvent and a
base to give Ranolazine of formula (I).
The organic solvent used is selected from aromatic hydrocarbon such as xylene, toluene,
preferably toluene. The base used is selected from alkali metal carbonates such as sodium
carbonate, potassium carbonate, preferably sodium carbonate or alkali metal bicarbonates like

lithium bicarbonate, sodium bicarbonate or potassium bicarbonate, preferably sodium bicarbonate. The Ranolazine base is further converted to Ranolazine dihydrochloride by reacting Ranolazine base with HC1.

wherein Rl is alkyl or aryl, and wherein alkyl is selected from methyl, ethyl, propyl or isopropyl,
t-butyl, preferably ethyl.
By using N-Carbethoxypiperazine derivative, dimer impurity formation is inhibited.
In addition to this the amount of N-carbethoxy piperazine/piperazine derivative used in both the
reaction scheme is in quantitative in amount i.e. 1.0-1.1 Molar proportion.

Having described the invention with reference to certain preferred embodiments, the other embodiments will become apparent to one skilled in the art from consideration of the
specification.
EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
Example 1 (Scheme A/B):
Preparation of [(2,6-Dimethylphenyl)-amino carbonyl methyl] chloride (II)
To 0.74 kg of potassium carbonate and 2,5L of water, was added 500 gm of 2,6-Dimethyl aniline in 1.25 L of Acetone at 0-5 °C. 650 gm of chloroacetyl chloride was added to the reaction mixture below 5 °C and stirred the reaction mixture for 3 hrs. 2500 ml of water was added, stirred for 1 hr, filtered the product, washed with water and dried at 75 °C to get [(2,6-Dimethylphenyl)-amino carbonyl methyljchloride (II). Yield: 95%; purity >98%
Example 2 (Scheme A/B):
Preparation of l-(2-Methoxy phenoxy)-2,3-epoxy propane (III)
Added 5L of water to a 10 L flask, 250 gm of sodium hydroxide was added and stirred to dissolve. Added 500 gm of Guaiacoh 1120 gm of Epichlorohydrin and stirred at 30-35 °C for 6 hrs. The organic layer was separated, distilled out Epichlorohydrin from the organic layer, added 1500 ml of toluene and 100 gm of sodium hydroxide and stirred for 1 hr. 1250 ml of water was added to it, stirred for 15 min and the organic layer was separated. The organic layer was washed thrice with 1000 ml water. Toluene was distilled out from the organic layer. Added 2500 ml of

isopropanol to it, stirred to get a clear solution, cooled to 0 °C and filtered the product to get 1 -(2-Methoxy phenoxy)-2,3-epoxy propane (III), Yield: 66%; purity >98%
Example 3 (Scheme A):
Preparation of [(2,6-dimethyl phenyl) amino carbonyl methyl]-4-carbethoxy piperazine
(IV)
To 800 ml of toluene, 100 gm of [(2,6-Dimethylphenyl)-amino carbonyl methyl] chloride (II) was added in a flask. Added 50 gms of sodium bicarbonate and 88 gms of N-Carbethoxy piperazine to the reaction mixture. The reaction mixture was refluxed for 8 hrs, cooled to 30 °C and 500 ml of water was added to it. The organic layer was separated and washed with water thrice. Toluene was distilled out from the organic layer to get [(2,6-dimethyl phenyl) amino carbonyl methyl]-4-carbethoxy piperazine (IV). Yield; 98%; purity >99%
Example 4 (Scheme A): Preparation of Ranolazine
To 375 ml of methanol, 75 gm of [(2,6-dimethyl phenyl) amino carbonyl methyI]-4-carbethoxy piperazine (IV) was added. A solution of 75 gm of KOH dissolved in 75 ml of water was added to the reaction mixture and refluxed for 16 hrs. Methanol was distilled out under reduced pressure. 100 ml of water and 150 ml of methylene chloride were added to it, stirred for 30 min and separated the organic layer. The aqueous layer was extracted twice with 150 ml of methylene chloride. The organic layers were mixed and 44 gm of l-(2-Methoxy phenoxy)-2,3-epoxy propane (III) was added to it and stirred for 1 hr. Distilled out Methylene chloride under reduced pressure, added 300 ml of isopropanol to the reaction mixture and refluxed for 2 hrs. Cooled the

reaction mixture to 0-5 °C, maintained it for 3 hrs, filtered the product, washed with chilled isopropanol and dried the product to get Ranolazine. Yield: 80%; purity >99% 140 gms of Ranolazine base was taken in 2160 ml Acetone and 100 ml IP A containing HC1 gas was added to it at room temperature and pH of reaction medium was adjusted to below 4. The precipitated dihydrochloride compound was filtered, washed with acetone and dried to give 144 gms Ranolazine dihydrochloride.
Example 5 (Scheme B):
Preparation of l-[3-(2-Methoxy phenoxy)-2-hydroxy propyl]-4-carbethoxy piperazine (VI)
To 250 ml of methanol, 50 gm of l-(2-methoxyphenoxy)-2,3-epoxy propane (III) and 44 gm of N-Carbethoxy piperazine were added and stirred the reaction for 24 hrs. Distilled out methanol under reduced pressure, 250 ml of methylene chloride and 200 ml of water was added to the reaction mixture. The organic layer was separated and washed with 200 ml of water. Distilled out Methylene chloride to get l-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-carbethoxy piperazine (VI). Yield: 100%
Example 6 (Scheme B):
Preparation of Ranolazine
To 250 ml of methanol, 94 gm of l-[3-(2-methoxyphenoxy)-2-hydroxy propyl]-4-carbethoxy piperazine (VI) was added. A solution of 75 gm of KOH dissolved in water was added to the reaction mixture, refluxed for 16 hrs, distilled out methanol under reduced pressure. Add 75 ml of water and 200 ml of methylene chloride to the reaction mixture. Stirred for 15 mins and separate the organic layer. The aqueous layer was extracted with 2 x 200 ml of methylene

chloride. The MDC layers were mixed and distilled out under vacuum. 350 ml of toluene, 28 gm of sodium bi carbonate and 54.8 gm of [(2, 6 -Dimethyl phenyl)-amino carbonyl methyl] chloride (II) were added to the reaction mixture and refluxed for 6 hrs. Added 300 ml of water to the reaction mixture, stirred for 15 mins and the organic layer was separated. To the toluene layer, aqueous HC1 (44 ml of coned HC1 + 300 ml of water) was added, stirred for 15 mins and the layers were separated. The aqueous layer was basified with dilute NaOH solution to get Ranolazine. Yield: >=77%; purity >95%.
140 gms of Ranolazine base was taken in 2160 ml Acetone and 100 ml IP A containing HC1 gas was added to it at room temperature and pH of reaction medium was adjusted to below 4. The precipitated dihydrochloride compound was filtered, washed with acetone and dried to give 144 gms Ranolazine dihydrochloride.

CLAIMS
We Claim:
1. A compound of the formula (IV):

wherein R is an alkyl or aryl group.
2. A compound of the formula (VI):

wherein Rl is an alkyl or aryl group.
3. Compound of claim 1, wherein alkyl is selected from methyl, ethyl, propyl or isopropyl, t-
butyl preferably ethyl.

4. Compound of claim 2, wherein alkyl is selected from methyl, ethyl, propyl or isopropyl, t-butyl, preferably ethyl.
5. A process for preparing compound of formula (IV)

wherein R is alkyl or aryl;
comprising reacting [(2,6-Dimethylphenyl)-amino carbonyl methyljchloride of formula (II)

with N-Carbethoxy piperazine
in presence of an organic solvent and a base.
6. A process according to claim 5, wherein organic solvent is selected from xylene, toluene or
mixtures thereof, preferably toluene.

7. A process according to claim 5, wherein the base is selected from alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate preferably sodium carbonate or alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium bicarbonate.
8. A process for preparing compound of formula (VI)

wherein Rl is alkyl or aryl;
comprising reacting l-(2-Methoxy phenoxy)-2,3-epoxy propane (III)

with N-Carbethoxy piperazine

in presence of an organic solvent.
9. A process according to claim 8, wherein organic solvent is selected from (CM) linear aliphatic alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol, preferably methanol.

10, A process according to claims 5 and 8, wherein the use of N-Carbethoxy piperazine inhibits
the formation of dimer impurity in the process.
11. A process for the preparation of Ranolazine of formula (I) and its acid addition salts thereof,

which comprises-
a. hydrolysis and concurrent decarboxylation of compound of formula (IV)

wherein R is same as per claim 1; with alkali to give l-[(2,6-dimethylphenyl)amino carbonyl methyl]piperazine of formula (V)


b. reacting compound of formula (V) with l-(2-Methoxy phenoxy)-2,3-epoxy propane of formula (III)
in presence of an organic solvent to give Ranolazine of formula (I).
12. A process according to claim 11, wherein in step a, the alkali used for hydrolysis is alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably potassium hydroxide.
13. A process according to claim 11, wherein in step a, the organic solvent used for hydrolysis is selected from aliphatic alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isobutanol, tert-butanol or mixtures thereof, preferably methanol.
14. A process according to claim 11, wherein in step b, the organic solvent selected from polar solvents like water, acetone, alcohols, preferably aliphatic alcohols like methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isobutanol, tert-butanol, more preferably isopropanol.
15. A process according to claim 11, wherein l-(2-Methoxy phenoxy)-2,3-epoxy propane of formula (III) is isolated as a solid having low melting point.

16. A process for the preparation of Ranolazine of formula (I) and its acid addition salts thereof, comprising
a. hydrolysis and concurrent decarboxylation of compound of formula (VI)

wherein Rl same as per claim 1; with alkali to give I-[3-(2-methoxyphenoxy)-2-hydroxypropyl]piperazine of formula (VII)

b. reacting compound of formula (VII) with [(2,6-dimethylphenyl)-aminocarbonyl
methyl] chloride of formula (II)


in presence of an organic solvent and a base to give Ranolazine of formula (I).
17. A process according to claim 16, wherein in step a, the alkali used for hydrolysis is selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably potassium hydroxide.
18. A process according to claim 16, wherein in step a, the organic solvent used for hydrolysis is selected from aliphatic alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol, preferably methanol.
19. A process according to claim 16, wherein in step b, the organic solvent selected from an aromatic hydrocarbon such as xylene, toluene, preferably toluene.
20. A process according to claim 16, wherein in step b, the base used is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate or alkali metal bicarbonates like lithium bicarbonate, sodium bicarbonate or potassium bicarbonate, preferably sodium bicarbonate.
21. An improved process according to ay of the preceding claims substantially as herein described with reference to the examples.