Improved Process for the Preparation of Pure Ranolazine and Its Pharmaceutically acceptable Salts
Field of the Invention:
The present invention relates to an improved process for the preparation of pure ranolazine and its pharmaceutically acceptable salts. It also relates to the isolation, characterization and synthesis of impurities in ranolazine. Ranolazine is chemically known as N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy) propyl]-l-piperazine acetamide, represented by the following structural formula-1.

Ranolazine is approved for the treatment of chronic angina. Because ranolazine prolongs the QT interval, it should be reserved for patients who have not received an adequate response with other antianginal drugs. Ranolazine differs from traditional antianginal agents (beta-blockers, calcium channel blockers and long-acting nitrates) in that its anti-anginal and antiischemic effects are independent of reductions in blood pressure and/or heart rate. Although the exact mechanism of action is not knovra, ranolazine is believed to reduce angina/ischemia by selectively inhibiting the late sodium current resulting in reduced intracellular sodium and calcium overload during ischemia. Ranolazine is available under the brand name Ranexa®. Ranexa is available for oral administration as film-coated, extended-release tablets containing 500 mg of ranolazine.
Background of the Invention:
Ranolazine, its pharmaceutically acceptable salts thereof and process for their preparation are disclosed in US 4567264. The disclosed process comprises of reacting 2-methoxy phenol with epichlorohydrin in presence of sodium hydroxide in a mixture of

dioxane and water gives l-(2-methoxyphenoxy)-2,3-epoxypropane with purity around 40%, which on reacting with piperazine in ethanol gives l-(2-methoxyphenoxy)-3-(piperazin-l-yl)propan-2-ol, followed by its condensation with [(2,6-dimethylphenyl)-amino carbonylmethyl] chloride in dimethylformamide gives ranolazine. Ranolazine obtained as on oil after purifying by column chromatography or reacting the free base with hydrochloric acid to get ranolazine dihydrochloride and converting it back into ranolazine. The yields and purity of the intermediate as well as the final compounds obtained by the above process are very low.
The product obtained by the chemical reaction is in most cases contaminated with the side products, by products of the reaction and unreacted starting materials or reagents used in the reaction and thereby limiting the product with sufficient purity to comply with pharmaceutical standards. In order to avoid/control the impurity formation in a chemical reaction/process for the preparation of drug product, for example ranolazine it must be analyzed for purity, such as by employing high performance liquid chromatography or thin layer chromatography or Gas chromatography techniques to determine the suitability of the particular stage purity for continuation to next stage for use in a pharmaceutical product. The US Food and Drug Administration requires that a drug substance is as free of impurities as possible, so that is as safe as possible for clinical use. For example it recommends that the amount of some impurities be limited to less than 0.1 percent.
Like any synthetic compound, ranolazine can contain extraneous compounds or impurities. These impurities may be, for example, unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. The purity of the drug product thus produced is critical in the preparation of drug substance.
Ranolazine may contain the impurity 3-(2-methoxyphenoxy)propane-l,2-diol, herein designated as "Impurity-A"; 3-3'-(piperazine-l,4-diyl)bis(l-(2-methoxyphenoxy) propan-2-ol), herein in designated as "Impurity-B"; impurity 2,2'-(piperazine-1,4-diyl)bis(N-(2,6-dimethylphenyl)acetamide), herein designated as "Impurity-C" and impurity l,3-bis(2-methoxyphenoxy)propan-2-ol, herein designated as "Impurity-D"; N-(2,6-dimethylphenyl)-2-(4-(2-(2-(2,6-dimethylphenylamino)-2-oxoethoxy)-3-(2-methoxy phenoxy)propyl)piperazin-1 -yl)acetamide, herein designated as "Impurity-E". The impurity A, B, C, D & E have the following structural formula respectively.


There is a need in the art to detect, isolate, characterize as well as to control the formation of these impurities in ranolazine and its pharmaceutically acceptable salts. In the present invention impurity-B, impurity-C and impurity-D were isolated and characterized.


The present invention provides an improved process for the preparation of pure ranolazine and its pharmaceutically acceptable salts without any column purification and salt purification. This present invention also provides isolation, characterization and synthesis of impurities in ranolazine and its pharmaceutically acceptable salts.
Brief Description of the Invention:
The present invention provides an improved process for the preparation of pure ranolazine and its pharmaceutically acceptable salts. It also provides isolation, characterization and synthesis of impurities in ranolazine. Ranolazine is chemically known as N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-l-piperazine acetamide compound represented by the following structural formula-1.

And its pharmaceutically acceptable salts.
The first aspect of the present invention provides a process for the preparation of ranolazine having each of l,3-bis(2-methoxyphenoxy)propan-2-ol, 3-3'-(piperazine-l,4-diyl)bis( 1 -(2-methoxyphenoxy )propan-2-ol and 2,2' -(piperazine-1,4-diyl)bis(N-(2,6-dimethylphenyl)acetamide) impurities less than about 0.15 % area by HPLC. The process comprise of the following steps:
a) reacting 2-methoxy phenol compound of formula-2 with epichlorohydrin compound
of formula-3 in presence of a suitable base in a suitable polar solvent gives epoxy
propane compound of formula-4,
b) reacting the epoxy propane compound of formula-4 with piperazine in a suitable
alcoholic solvent gives the condensed compound of formula-5 free of impurity-B,
c) reacting the dimethyl aniline compound of formula-6 with chloro acetyl chloride in a
suitable solvent gives chloro compound of formula-7,

d) reacting the condensed compound of formula-5 with chloro compound of formula-7 in presence of a suitable base in a suitable solvent gives ranolazine compound of formula-1,
e) optionally purifying ranolazine using suitable solvents selected from alcohol or ester solvent or ketone solvents or mixture of solvents or converting into to its pharmaceutically acceptable salts by conventional methods.
The second aspect of the present invention is to provide 3-3'-(piperazine-1,4-diyl)bis(l-(2-methoxyphenoxy)propan-2-ol (Impurity-B), 2,2'-(piperazine-l,4-diyl)bis (N-(2,6-dimethylphenyl)acetamide) (Impurity-C) and l,3-bis(2-methoxyphenoxy)propan" 2-ol (Impurity-D). We the present inventors detected, isolated and characterized the said impurities which were observed in the synthesis of ranolazine and its pharmaceutically acceptable salts.
The third aspect of the present invention is to provide a process for the preparation of 3 -3' -(piperazine-1,4-diyl)bis( 1 -(2-methoxyphenoxy)propan-2-ol. The process comprises of reacting l-(2-methoxyphenoxy)-2,3-epoxypropane with piperazine in a suitable alcoholic solvent and maintaining the mixture for a period of time sufficient to obtain 3-3'-(piperazine-1,4-diyl)bis( 1 -(2-methoxyphenoxy)propan-2-oL
The fourth aspect of the present invention is to provide a process for the preparation of 2,2'-(piperazine-l,4-diyl)bis(N-(2,6-dimethylphenyl)acetamide). The comprises of reacting l-(2-methoxyphenoxy)-2,3-epoxypropane with piperazine in a suitable alcoholic solvent and maintaining the mixture for a sufficient period of time to obtain 3-3'-(piperazine-l,4-diyl)bis(l-(2-methoxyphenoxy)propan-2-ol.
The fifth aspect of the present invention is to provide a process for the preparation of l,3-bis(2-methoxyphenoxy)propan-2-ol. The process comprises of reacting 2-methoxyphenol and epichlorohydrin in a suitable base in a suitable polar solvent and maintaining the mixture for a sufficient period of time to obtain l,3-bis(2-methoxyphenoxy)propan-2-ol.

Advantageous of the Present invention:
• Provides impurity-B, impurity-C and impurity-D of ranolazine and its pharmaceutically acceptable salts, which were isolated, characterized and used to determine the purity of ranolazine and also to quantify the amount of impurity-B, impurity-C and impurity-D present in ranolazine and its pharmaceutically acceptable salts.
• Provides an improved process for the preparation of ranolazine and its intermediate compounds with high purity and yield.
• Provides pure ranolazine compound having each of the impurity-B, impurity-C and impurity-D less than 0.15% area by HPLC.
• Eco-friendly, cost effective and commercially viable process.
Brief Description of the Drawings:
Figure-1: Powder X-ray diffraction chromatogram of ranolazine
Figure-2: HPLC chromatogram of pure ranolazine
Figure-3: HPLC chromatogram of blended ranolazine with impurities
Detailed Description of the Invention:
The present invention provides an improved process for the preparation of pure
ranolazine and its pharmaceutically acceptable salts. It also provides isolation,
characterization and synthesis of impurities in ranolazine. Ranolazine is chemically
known as N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy) propyl-l-
piperazine acetamide, compound represented by the following structural formula-1.
CH3
Formula-1 and its pharmaceutically acceptable salts.
%

The first aspect of the present invention provides an improved process for the preparation of pure ranolazine and its pharmaceutically acceptable salts containing each of the impurity-B and impurity-C and impurity-D less than 0.15 % area by HPLC, which comprises of the following steps:

c) reacting the dimethyl aniline compound of formula-6

e) optionally purifying ranolazine using suitable solvent selected from alcoholic solvent like methanol, ethanol, isopropyl alcohol, ester solvent like ethyl acetate or ketone solvent like actone or converting into its pharmaceutically acceptable salts by treating the ranolazine with suitable acid in a suitable solvent or by methods known in the art.
The second aspect of the present invention provides 3-3'-(piperazine-l,4-diyl)bis(l-(2-methoxyphenoxy)propan-2-ol (Impurity-B), 2,2'-(piperazine-l,4-diyl)bis (N-(2,6-dimethylphenyl)acetamide) (Impurity-C) and l,3-bis(2-methoxyphenoxy)propan-2-ol (Impurity-D) which are observed in the synthesis of Ranolazine and its pharmaceutically acceptable salts. Impurity-B, Impurity-C and Impurity-D of ranolazine are represented by the following structural formulas;

3-3'-(piperazine-l,4-diyl)bis(l-(2-methoxyphenoxy)propan-2-ol (Impurity-B), 2,2'-(piperazine-l,4-diyl)bis(N-(2,6-dimethylphenyl)acetamide)(Impurity-C) and 1,3-bis (2-methoxyphenoxy)propan-2-ol (Impurity-D) of the present invention are characterized by NMR, IR and Mass spectral data.

The third aspect of the present invention provides a process for the preparation 3-3'-(piperazine-l,4-diyl)bis(l-(2-niethoxyphenoxy)propan-2-ol, which comprises of the following steps;
a) reacting 1 -(2-niethoxyphenoxy)-2,3-epoxypropane

with piperazine in a mole ratio of 0.5 to 0.9 in a suitable alcoholic solvent like methanol, ethanol, isopropyl alcohol preferably methanol at a temperature 0-10°C, preferably 0-5°C,
b) stirring the reaction mixture for a sufficient period of time preferably 2-10 hours, more preferably 2-8 hours to obtain 3-3 '-(piperazine-1,4-diyl)bis(l -(2-methoxyphenoxy)propan-2-ol,
c) separating the solid by filtration,
d) drying the solid gives 3-3'-(piperazine-l,4-diyl)bis(l-(2-methoxyphenoxy)propan-2-ol,
The fourth aspect of the present invention provides a process for the preparation of 2,2'-(piperazine-l,4-diyl)bis(N-(2,6-dimethylphenyl)acetamide), which comprise of the following steps; a) reacting 2-chloro-N-(2,6-dimethylphenyl)acetamide

with piperazine in the mole ratio of 0.5 to 0.9 in a suitable alcoholic solvent selected from methanol, ethanol, isopropyl alcohol preferably methanol in a presence of a suitable base like triethylamine at temperature of about 30-70°C, preferably at 55-65X,

b) stirring the reaction mixture for a sufficient period of time preferably 2-20 hours, more preferably 2-18 hours at reflux temperature to obtain 2,2'-(piperazine-l,4-diyl)bis(N-(2,6-dimethylphenyl)acetamide),
c) cooling the reaction mixture to room temperature,
d) separating the solid by filtration,
e) drying the solid gives 2,2'-(piperazine-l,4-diyl)bis(N-(2,6-dimethylphenyl) acetamide).
The fifth aspect of the present invention provides a process for the preparation of l,3-bis(2-methoxyphenoxy)propan-2-ol, which comprises of the following steps:
a) reacting 2-methoxy propanol

with epichlorohydrin in a suitable polar solvent like water in a presence of a suitable base like sodium hydroxide at temperature of about 35-55°C, preferably at 40-45°C,
b) stirring the reaction mixture for a sufficient period of time preferably 2-10 hours, more preferably 2-9 hours at 40-45°C to obtain l,3-bis(2-methoxyphenoxy)propan-2-ol,
c) cooling the reaction mixture to room temperature,
d) extracting the reaction mixture with suitable chloro solvent like methylene chloride,
e) distilling off the solvent at below 40°C to get l,3-bis(2-methoxyphenoxy) propan-2-ol.
The sixth aspect of the present invention provides ranolazine substantially fine of impurities. Substantially pure ranolazine meant that ranolazine prepared according to the present invention contains less than about 0.15% preferably less than about 0.1 % and more preferably 0.05% of impurity-B and impurity-C, impurity-D as characterized by high performance liquid chromatography obtained from a mixture comprising the desired compound and one or more of the said impurities. The percentage here refers to the area percent of the peaks representing the said impurities.

Ranolazine and its pharmaceutically acceptable salts can be milled or Micronized to reduce the particle size.
The IR spectrum of impurities was recorded on TEC Nicolet 380 model FT-IR as KBr pellet.
The mass spectrum of impurities was recorded on positive AL MS by mass spectrometer.
The ^H NMR data was recorded in CDCI3 solvent on Avance 300 MHz spectrometer using TMS as internal standard.
High Performance Liquid Chromatography (HPLC) of ranolazine is carried out to find out the related substances using a liquid chromatograph equipped with variable wavelength UV-detector, column Luna C8, 250 x 4.6 mm, 5|a or equivalent, at a wavelength of 220 nm with a flow rate of 1 ml/min, at 25°C temperature, load is 10 runtime is 50 minutes, the diluent is mobile phase-A; Mobile phase A is Buffer and acetonitrile in the ratio of 80:20 and Mobile phase-B is acetonitrile:water in the ratio of 70:30. The buffer is prepared by dissolving 1.56 grams of sodium dihyrogen orthophosphate dehydrate in 500 ml of water, diluted with water to 1000 ml, and mixed, and adjusted the pH to 3 with dilute phosphoric acid.

Analysis of particle size distribution of ranolazine: A Malvern laser diffraction instrument was used to characterize the particle size distribution of ranolazine. Instrument model: Malvern Masteries 2000 Technique used: Wet method

Instrument parameters:
i) Material RI: 1.45
ii) Dispersant RI: 1.468
iii) Dispersant: Light liquid paraffin
iv) Sensitivity: Normal
v) Particle shape : Irregular
vi) Stirrer speed : 2800 rpm


The processes described in the present invention were demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1:
Preparation of l,-(2-methoxyphenoxy)-2,3-epoxypropane:
Epichlorohydrin (10.5 grams) was added to a mixture of 2-methoxy phenol (10 grams), water (60 ml) and sodium hydroxide (3.5 grams) at 25-30°C. The reaction mixture was heated 40-45°C. The reaction mixture was stirred for 5 hours at 40-45°C. The reaction mixture was cooled to 25-30°C followed by extraction with methylene chloride. The organic layer was washed with water. The solvent from the organic layer distilled under reduced pressure at below 40°C to get the title compound. Yield: 13.5 grams Purity by HPLC: 88.00%
Example-2:
Preparation of l-(2-methoxyphenoxy)-3-(piperazine”l-yl)propan-2-ol:
A mixture of piperazine (95.7 grams) and methanol (250 ml) was cooled to 0-5°C. l,-(2-methoxyphenoxy)-2,3-epoxypropane (50 grams) was slowly added to the above reaction mixture 0-5 °C. The reaction mixture was stirred for 3 hours at 3-4°C. The reaction mixture was filtered through the Hyflow to remove the dimmer impurity. The solvent from the filtrate was distilled off under reduced pressure at below 60°C. The reaction mixture was cooled to 25-30°C. Water (250 ml) was added to the above reaction mixture. The pH of the reaction mixture was adjusted to 6.3 with acetic acid. The reaction mixture was washed with methylene chloride to remove the dimer impurity. The pH of the aqueous layer was adjusted to 10.5 using aqueous sodium hydroxide solution. The reaction mixture was extracted with methylene chloride. The solvent from the organic layer was distilled off completely under the reduced pressure at below 40°C. Yield: 58 grams. Purity by HPLC: 98.00%

Example-3:
Preparation of [(2,6-dimethylphenyl)-amino carbonylmethyl]chloride:
Chloroacetyl chloride (51.5 grams) was added to a mixture of 2,6-dimethylaniline (50 grams) and dichloromethane (750 ml) at 25-35°C. The reaction mixture was stirred for 3 hours at 25-35°C. The reaction mixture was washed with water followed by aqueous hydrochloric acid solution. Washed the reaction mixture with water. The solvent from the reaction mixture was distilled off completely under reduced pressure at below 40°C. Cyclohexane (200 ml) was added to the reaction mixture. The reaction mixture was stirred for 45 minutes. The reaction mixture was filtered and washed with cyclohexane. The obtained solid was dried at 50-55°C to get the title compound. Yield: 76 grams Purity by HPLC: 99.00 %
Exampie-4:
Preparation of pure crystalline Ranolazine:
A mixture of l-(2-methoxyphenoxy)-3-(piperazin-l-yl)propan-2-ol (93 grams), triethylamine (46 grams) and [(2,6-dimethylphenyl)-amino carbonylmethyl]chloride (89.5 grams) in methanol (465 ml) was heated to reflux temperature 60-65°C. The reaction mixture was stirred for 15 hours at reflux temperature. The solvent from the reaction mixture was distilled off completely under reduced pressure at below 60°C. The reaction mixture was cooled to 25-35°C. Water (400 ml) was added to the reaction mixture followed by methylene chloride (450 ml) at 25-35°C. The reaction mixture pH was adjusted to 5.4 with acetic acid at 25-30°C. The organic and aqueous layers were separated. The organic layer washed with water. Water (1120 ml) was added to the above organic layer. The pH of the reaction mixture was adjusted to 1.4 using hydrochloric acid. The reaction mixture was washed with methylene chloride. The aqueous layer pH was adjusted to 7.4 with aqueous sodium carbonate solution. The reaction mixture was extracted with methylene chloride. The solvent from the reaction mixture was distilled off under reduced pressure at below 40°C. Methanol (93 ml) was added to the reaction mixture and distilled off under reduced pressure at below 60°C. Methanol (370 ml) was added to the reaction mixture and treated with 5.5 grams carbon. The reaction mixture

was heated to reflux at 65°C and stirred at reflux temperature for 45 minutes. The
reaction mixture was filtered through Hyflow and washed the bed with methanol. The
filtrate was cooled to 0-5°C. Stirred the reaction mixture for 1.5 hours at 0-5°C. The solid
formed is filtered and washed with methanol. The solid was dried at 60-65°C to get the
title compound.
Yield: 93 grams
Purity by HPLC: 99.79%
Impurity-A: 0.02%
Impurity-B: Not detected
Impurity-C: Not detected
Impurity-D: Not detected
Particle Size distribution: D is 3.554 ^im; D(0.5) is 68.975 ^im; D(0.9) is 141.19
fim and Mean D[4,3] is 69.1
ExampIe-5:
Purification of ranolazine:
A mixture of Ranolazine (22 grams) and methanol (110 ml) was heated to reflux temperature of 60-65°C. The reaction mixture was stirred at 60-65°C for 30 minutes. The reaction mixture slowly cooled to 0-5°C. The reaction mixture was stirred for 1.5 hours at 0-5°C. The solid formed is filtered and washed with methanol. The solid was dried at 60-65°C to get the title compound. Yield: 20 grams
Particle Size Distribution: D(O.l) is 2.693 ^m; D(0.5) is 47.05 ^m; D(0.9) is 143.14 ^m; D(l.O) is 259.50 ^m and Mean D[4,3] is 59.507 [im.
Example-6:
Preparation of ranolazine dihydrochloride:
A mixture of ranolazine (8 grams) and methanol (10 ml) was cooled to 15-20°C. The pH of the reaction mixture was adjusted to 1.5 by passing hydrochloride gas. The reaction mixture was cooled to 0-5°C. The reaction mixture was stirred for 2 hours at 0-5°C. The solid formed is filtered and washed with methanol. The solid was dried at 50-55°C to get the title compound.

Yield: 6 grams
Purity by HPLC: 99.85%
Example-7:
Preparation of 3-3'-(piperazine-l,4-diyl)bis(l-(2-methoxyphenoxy)propan-2-oI
(Impurity-B):
Piperazine (2.39 grams) was dissolved in methanol (50 ml) at 25-30°C. The reaction mixture was cooled to 0-5°C. l-(2-methoxyphenoxy)-2,3-epoxypropane was added to the above reaction mixture at 0-5°C. Stirred the reaction mixture for 8 hours at 0-5°C. The solid obtained was filtered. Dried the material at 40-45''C to get the title compound. Yield: 9.7 grams.
Mass spectrum: [M^+1] Peak at m/z 447.3
*H NMR (6): 2.4-2.7 (m, 12H), 3.5 (s, 2H); 3.8-3.9 (s, 6H), 4.0-4.05 (d, 4H), 4.1-4.2 (m, 2HX 6.85-7.0 (m, 8H). IR(cm-^): 3171,2931, 1589,1504,1083.
Example-8:
Preparation of 2,2'-(piperazine-l,4-diyl)bis(N-(2,6-dimethylphenyl)acetamide)
(Impurity-C).
Mixture of 2-chloro-N-(2,6-dimethylphenyl)acetamide (10 grams), piperazine (2.6 grams), triethylamine (7 ml) and methanol (150 ml) was stirred for 5 hours at 25-30°C. The reaction mixture was heated to reflux and stirred at reflux for 18 hours. The reaction mixture was cooled to 30-35°C. Filtered the solid obtained and dried at 40-45 °C to get the title compound. Yield: 7 grams
Mass spectrum: [M'^+1] Peak at m/z 409.3
*HNMR (6): 2.25 (s, 12H), 2.8 (s, 8H), 3.25(s, 4H), 7.1 (s, H), 8.56 (s, 2H). IR(cm"'): 3302, 3011, 2942, 1650, 1499.

Example-9:
Preparation of l,3-bis(2-methoxyphenoxy)propan-2-ol (Impurity-D):
A mixture of 2-methoxyphenol (10 grams), epichlorohydrin (3.7 grams), sodium hydroxide (3.7 grams) and water (60 ml) was heated to 45-48°C. The reaction mixture was stirred for 8 hours 30 minutes at 45-48°C. The reaction mixture was cooled to 30-35°C. The reaction mixture was extracted twice with methylene chloride. The methylene chloride layer was distilled off completely under reduced pressure at below 40°C to get the title compound. Yield: 12.5 grams
Mass spectrum: [M'^+1] Peak at m/a 305.5 *H NMR (5): 3.8-3.9 (s, 6H); 4.15-4.3 (m, 4H), 4.4-4.5 (s, IH), 6.85-7.0 (m, 8H).

We Claim:
1. 3-3'-(piperazine-l,4-diyl)bis(l-(2-methoxyphenoxy)propan-2-ol (Impurity-B) having
the following structural formula

Which is characterized by the data selected from
Mass spectrum: [M" +l] Peak at m/z 447.3,
*H NMR (6): 2.4-2.7 (m, 12H), 3.5 (s, 2H); 3.8-3.9 (s, 6H), 4.0-4.05 (d, 4H), 4.1-4.2
(m, 2H), 6.85-7.0 (m, 8H),
IR(cm'^): 3171,2931, 1589, 1504, 1083.
2. A process for the preparation of 3 -3' -(piperazine-1,4-diyl)bis( 1 -(2-
methoxy phenoxy)propan-2-ol comprise of the following steps,
a) reacting l-(2-methoxyphenoxy)-2,3-epoxypropane

with piperazine in the mole ratio of 0.5 to 0.9 in a suitable alcoholic solvents like methanol, ethanol and isopropyl alcohol,
b) stirring the reaction mixture for a sufficient period of time preferably 2-10 hours to obtain 3-3' -(piperazine-1,4-diyl)bis( 1 -(2-methoxyphenoxy)propan-2-ol,
c) separating the solid by filtration,
d) drying the solid gives 3 -3' -(piperazine-1,4-diyl)bis( 1 -(2-methoxyphenoxy)
propan-2-ol.
3. 2,2'-(piperazine-l,4-diyl)bis(N-(2,6-dimethylphenyl)acetamide) (Impurity-C) having
the following structural formula.


Which is characterized by the data selected from
Mass spectrum: [M'^+1] Peak at m/z 409.3,
*H NMR (6): 2.25 (s, 12H), 2.8 (s, 8H), 3.25(s, 4H), 7.1 (s, H), 8.56 (s, 2U),
IR (cm-^): 3302, 3011, 2942,1650, 1499.
4. A process for the preparation of 2,2'-(piperazine-l,4-diyl)bis(N-(2,6-dimethyl
phenyl)acetamide) comprises of the following steps;
a) reacting 2-chloro-N-(2,6-dimethylphenyl)acetamide

with piperazine in the mole ratio of 0.5 to 0.9 in a suitable alcoholic solvent selected from methanol, ethanol, isopropyl alcohol in a presence of a suitable base like triethylamine at temperature of about 30-70°C,
b) stirring the reaction mixture for a sufficient period of time preferably 2-20 hours at reflux temperature to obtain 2,2' -(piperazine-1,4-dilyl)bis(N-(2,6-dimethylphenyl) acetamide),
c) cooling the reaction mixture to room temperature,
d) separating the solid by filtration,
e) drying the solid gives 2,2'-(piperazine-l,4-dilyl)bis(N-(2,6-dimethylphenyl)
acetamide).
5. l,3-bis(2-methoxyphenoxy)propan-2-ol (Impurity-D) having the following structural
formula


Which is characterized by the data selected from
Mass spectrum: [M"^+l] Peak at m/a 305.5,
^HNMR (6): 3.8-3.9 (s, 6H); 4.15-4.3 (m, 4H), 4.4-4.5 (s, IH), 6.85-7.0 (m, 8H).
6. A process for the preparation of l,3-bis(2-methoxyphenoxy)propan-2-ol comprises of
the following steps:
a) reacting 2-methoxy propanol

•J with epichlorohydrin in a suitable polar solvent like water in a presence of a
suitable base like sodium hydroxide at temperature of about 35-55°C, preferably
at 40-45°C,
b) stirring the reaction mixture for a sufficient period of time preferably 2-10 hours,
more preferably 2-9 hours at 40-45°C to obtain l,3-bis(2-
methoxyphenoxy)propan-2-ol,
c) cooling the reaction mixture to room temperature,
d) extracting the reaction mixture with suitable chloro solvent like methylene chloride,
e) distilling off the solvent at below 40°C to get l,3-bis(2-methoxyphenoxy)propend-
2-ol.
7. An improved process for the preparation of pure ranolazine and its pharmaceutically
acceptable salts compound of formula-1 containing each of impurity-B, impurity-C
and impurity-D less than 0.15 % area by HPLC, independently,


in presence of a suitable alkali metal hydroxide like sodium hydroxide or potassium hydroxide in a suitable polar solvent selected from water, dimethyl sulfoxide gives epoxy propane compound of formula-4,

b) reacting the epoxypropane compound of formula-4 with piperazine in a suitable alcoholic solvent like methanol, ethanol and isopropyl alcohol followed by washing with suitable chloro solvent like methylene chloride to remove the impurity-B gives the condensed compound of formula-5 free of impurity-B,

e) optionally purifying ranolazine using suitable solvent selected from alcoholic solvent like methanol, ethanol, isopropyl alcohol, ester solvent like ethyl acetate, ketone solvents like acetone, butanone or mixtures thereof or converting into its pharmaceutically acceptable salts by conventional methods.
8. Ranolazine and its pharmaceutically acceptable salts containing each of impurity-B,
impurity-C and impurity-D less than 0.15 area percent by HPLC, independently.
9. The use of isolated impurity-B, impurity-C and Impurity-D as a reference standard
and reference marker to determine the amount of impurity-B, impurity-C and
Impurity-D in ranolazine and to analyze its purity.
10. Ranolazine having a particle size distribution Diol less than 20|im; D50 less than 85
|im; D90 less than 300 and the mean particle size D(4,3) less than 80 |am.