DESC:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION:

“A PROCESS FOR THE PREPARATION OF HIGHLY PURE TRAZODONE OR SALT THEREOF”

2. APPLICANT(S):

a) NAME: Ami Lifesciences Private Limited

b) NATIONALITY: An Indian Company registered under The Companies Act, 1956

c) ADDRESS: 7th Floor, Lilleria 1038, Gotri Sevasi Road, New Alkapuri, Vadodara – 390 021, Gujarat, India.

3. PREAMBLE TO THE INVENTION:

COMPLETE:

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 an efficient and industrially advantageous process for the preparation of highly pure Trazodone or salt thereof.
The present invention also relates to an improved processes for the preparation of Trazodone intermediates namely 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II, 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III, and 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV or salt thereof.
BACKGROUND OF THE INVENTION:
Trazodone is chemically known as 2-[3-[4-(3-chlorophenyl)-1- piperazinyl]propyl]-1,2,4-triazolo [4,3-a]pyridin-3(2H)-one, having the structure of Formula-I,

[Formula-I]
Trazodone was developed by Pragma Pharmaceuticals LLC and was approved in the form of hydrochloride salt by USFDA on Dec. 24, 1981, under the proprietary name Desyrel®. Trazodone is a selective serotonin reuptake inhibitor indicated for the treatment of major depressive disorder (MDD).
US patent number US3381009 (herein after US’009) first discloses s-triazolo-[4,3-a]-pyridine derivatives including Trazodone. US’009 also discloses a process for the preparation of Trazodone hydrochloride which involves condensation of [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one with l-(3-chlorophenyl)-4-(3-chloropropyl)piperazine in the presence of sodium hydride using dioxane as a solvent, followed by work-up with ether, treatment with etheral hydrochloride and crystallization from alcohol to obtain Trazodone hydrochloride.
Major drawback of US’009 process is, it requires sodium hydride, which is a flammable and reactive chemical. Further, US’009 process involves use of ether and ethereal hydrochloride during work-up which is commercially not viable. Overall process of US’009 is silent about genotoxic impurities and fails to control the level of genotoxic impurities in the Trazodone hydrochloride. Therefore, US’009 process is not an attractive option to use for industrial scale.
US patent number US4254124 (herein after US’124) discloses process for the preparation of [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one comprising condensation reaction of 2-chloropyridine with semicarbazide hydrochloride in presence of 2-ethoxyethanol and concentrated sulfuric acid.
Major drawback of US’124 process is, it requires organic solvent 2-ethoxyethanol. Also the process results into lower yield and fails to provide pure [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. Therefore, US’124 process is not an attractive option to use for industrial scale.
Indian patent number IN392264 (herein after IN’264) discloses a process for the preparation of Trazodone and its hydrochloride salt which involves condensation of 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine with sodium salt of [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one in presence of sodium carbonate, tetra-n-butylammonium bromide and isopropyl alcohol to obtain crude trazodone followed by further treatment with isopropanolic hydrochloride to obtain Trazodone hydrochloride.
Major drawback of IN’264 process is, it requires both inorganic base and phase transfer catalyst during the condensation reaction. Additionally, IN’264 process requires use of higher amount of inorganic base with respect to the 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine. Therefore, IN’264 process is not an attractive option to use for industrial scale.
PCT application number WO2017166050 (herein after WO’050) discloses a process for the preparation of Trazodone comprising condensation of 1-(3-chlorophenyl)-4-(3-chloropropyl) piperazine with 1,2,4-triazolo[4, 3-a]pyridine-3- (2H)-one in presence of isopropanol and sodium hydroxide.
Major drawback of WO’050 process is, the reaction time of 26 hours for completion. Also, the process requires further treatment with base by refluxing for additional 8 hours. Therefore, WO’050 process is not an attractive option to use for industrial scale.
Prior art discussed above suffers from many disadvantages like low purity, lengthy process, tedious work up, fails to control genotoxic impurity, which affect the overall yield as well as the purity of the final Trazodone product. Therefore, there is an urgent need for an improved process for the preparation of Trazodone having high purity which overcomes the drawbacks of the prior arts process.
The present inventors have developed an improved, efficient, and commercially scalable process for the preparation of Trazodone and its intermediates that addresses the problems associated with the processes reported in the prior art and provides highly pure Trazodone or salt thereof and its intermediates with control of impurities inclusive of genotoxic impurities.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide an efficient and industrially advantageous process for the preparation of highly pure Trazodone of Formula-I,

[Formula-I]
or salt thereof.
Another object of the present invention is to provide process for the preparation of Trazodone intermediates namely 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II, 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III, and 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV or salt thereof.

SUMMARY OF INVENTION:
First aspect of the present invention is to provide a process for the preparation of highly pure Trazodone of Formula-I,

[Formula-I]
or salt thereof, comprising the steps of:
a) reacting 3-chloroaniline with bis-(2-chloroethylamine) hydrochloride in presence of alkali metal hydroxide and water to obtain 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II;

[Formula-II]
b) reacting 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II with 1-bromo-3-chloropropane in presence of base and water to obtain a mixture;
c) treating mixture obtained in step b) with acid in presence of aromatic hydrocarbon solvent;
d) isolating pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
containing less than 0.1% of dimer Impurity-H,

[Impurity-H]
after treatment with base;
e) reacting pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III
with 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV,

[Formula-IV]
or salt thereof in presence of 4-dimethylaminopyridine and solvent to obtain highly pure Trazodone of Formula-I or salt thereof.
Second aspect of the present invention is to provide a process for the preparation of highly pure 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II,

[Formula-II]
comprising reacting 3-chloroaniline with bis-(2-chloroethylamine) hydrochloride in presence of alkali metal hydroxide and water to obtain 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II.
Third aspect of the present invention is to provide highly pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
containing less than 0.1% of dimer Impurity-H,

[Impurity-H].

Fourth aspect of the present invention is to provide a process for the preparation of highly pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
containing less than 0.1% of dimer Impurity-H,

[Impurity-H]
comprising the steps of:
a) reacting 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II,

[Formula-II]
with 1-bromo-3-chloropropane in presence of base and water to obtain a mixture;
b) treating mixture obtained in step a) with acid in presence of aromatic hydrocarbon solvent;
c) isolating pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III, containing less than 0.1% of dimer Impurity-H, after treatment with base.
Fifth aspect of the present invention is to provide a process for the preparation of highly pure Trazodone of Formula-I,

[Formula-I]
or salt thereof, comprising reacting 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
with 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV

[Formula-IV]
or salt thereof, in presence of 4-dimethylaminopyridine and solvent to obtain highly pure Trazodone of Formula-I or salt thereof.
Sixth aspect of the present invention is to provide a process for the preparation of highly pure 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV,

[Formula-IV]
or salt thereof, comprising reacting 2-chloropyridine with semicarbazide hydrochloride in presence of acid, phase transfer catalyst, and water to obtain 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV or salt thereof.
Seventh aspect of the present invention is to provide a process for the preparation of highly pure 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II,

[Formula-II]
comprising the steps of:
a) reacting 3-chloroaniline with bis-(2-chloroethylamine) hydrochloride in presence of aromatic hydrocarbon solvent to obtain 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II;

[Formula-II]
b) treating 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II with base in presence of water to obtain 1-(3-chlorophenyl)piperazine;
c) isolating 1-(3-chlorophenyl)piperazine by extraction with aromatic hydrocarbon solvent;
d) treating 1-(3-chlorophenyl)piperazine with hydrochloric acid in presence of aromatic hydrocarbon solvent to obtain highly pure 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II.
Eighth aspect of the present invention is to provide a process for the preparation of highly pure Trazodone hydrochloride of Formula-V,

[Formula-V]
comprising the steps of:
a) dissolving Trazodone of Formula-I,

[Formula-I]
in isopropyl alcohol;
b) adding hydrochloric acid to solution obtained in step a);
c) isolating Trazodone hydrochloride of Formula-V.
Ninth aspect of the present invention is to provide crystalline form AL-1 of Trazodone characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-1.
Tenth aspect of the present invention is to provide crystalline form AL-2 of Trazodone hydrochloride characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-2 and Differential scanning calorimetry (DSC) chromatograph as shown in Figure-3.
BRIEF DESCRIPTION OF DRAWINGS:
Figure-1: X-ray powder diffractogram (XRPD) of crystalline form AL-1 of Trazodone.
Figure-2: X-ray powder diffractogram (XRPD) of crystalline form AL-2 of Trazodone hydrochloride.
Figure-3: Differential scanning calorimetry (DSC) of crystalline form AL-2 of Trazodone hydrochloride.
DETAILED DESCRIPTION OF INVENTION:
While the following specification describes the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description and by studying the included examples.
The methods and materials of performing the present invention are described here.
The present invention provides a novel, efficient and industrially advantageous process for the preparation of highly pure Trazodone of Formula-I or salt thereof.
According to first embodiment, the present invention provides a process for the preparation of highly pure Trazodone of Formula-I,

[Formula-I]
or salt there of comprising the steps of:
a) reacting 3-chloroaniline with bis-(2-chloroethylamine) hydrochloride in presence of alkali metal hydroxide and water to obtain 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II;

[Formula-II]
b) reacting 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II with 1-bromo-3-chloropropane in presence of base and water to obtain a mixture;
c) treating mixture obtained in step b) with acid in presence of aromatic hydrocarbon solvent;
d) isolating pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
containing less than 0.1% of dimer Impurity-H,

[Impurity-H]
after treatment with base;
e) reacting pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,
with 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV,

[Formula-IV]
or salt thereof in presence of 4-dimethylaminopyridine and solvent to obtain highly pure Trazodone of Formula-I or salt thereof.
In the first embodiment of step a), 3-chloroaniline and bis-(2-chloroethylamine) hydrochloride used as a starting material for the preparation of Trazodone of Formula-I can be prepared by process known in the prior art.
In the first embodiment of step a), 3-chloroaniline can be reacted with bis-(2-chloroethylamine) hydrochloride in presence of alkali metal hydroxide and water to obtain 1-(3-chlorophenyl)piperazine hydrochloride.
In the first embodiment of step a), alkali metal hydroxide can be selected from the group consisting of sodium hydroxide, potassium hydroxide, or lithium hydroxide.
In the first embodiment of step a), molar equivalent of bis-(2-chloroethylamine) hydrochloride with respect to 3-chloroaniline can be in the range of 1.0 to 1.5.
In the first embodiment of step a), reaction of 3-chloroaniline with bis-(2-chloroethylamine) hydrochloride can be carried out at a temperature of 60°C to 110°C, preferably at 90°C to 110°C for a period of 2 hours to 6 hours.
In the first embodiment of step a), obtained 1-(3-chlorophenyl)piperazine hydrochloride can be treated with base in presence of water at 60°C to 80°C to obtain 1-(3-chlorophenyl)piperazine. Base can be selected from the group consisting of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide. Resulting 1-(3-chlorophenyl)piperazine can be extracted with solvent such as aromatic hydrocarbon solvent for example, benzene, toluene, or xylene and can be further treated with hydrochloric acid to obtain 1-(3-chlorophenyl)piperazine hydrochloride. Hydrochloric acid can be used in the form of solution or in the form of gas. Solution of hydrochloric acid can be concentrated or dilute. Hydrochloric acid (HCl) can also be used in the form of alcoholic solution of hydrochloric acid selected from the group consisting of methanolic HCl, ethanolic HCl, or isopropanolic HCl.
1-(3-chlorophenyl)piperazine hydrochloride can be isolated by technique of isolation methods known in the prior art, such as cooling, crystallization, recrystallization, or solvent-anti solvent methods; preferably by cooling to 0oC to 10°C over a period of 1 hour to 2 hours.
Bis-(2-chloroethylamine) hydrochloride defined herein after as Impurity-1,

[Impurity-1]
used in first embodiment of step a), itself is a genotoxic in nature. Therefore, control of Impurity-1 in 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II in intermediate step is very important. Inventors of the present invention controls this impurity at intermediate step below the level of detection.
Resulting 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II can have purity greater than 99%, preferably greater than 99.9% by HPLC (High-performance liquid chromatography).
In the first embodiment of step b), 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II can be reacted with 1-bromo-3-chloropropane in presence of base and water to obtain mixture containing 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine.
In the first embodiment of step b), molar equivalent of 1-bromo-3-chloropropane with respect to 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II can be in the range of 1.0 to 1.6
In the first embodiment of step b), base can be selected from the group consisting of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate.
In the first embodiment of step b), reaction of 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II with 1-bromo-3-chloropropane can be carried out at a temperature of 20oC to 60oC, preferably at 30oC to 40oC for a period of 15 hours to 20 hours. After completion of reaction, acid can be added to resulting mixture containing 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine to adjust the pH between 8 and 9.
In the first embodiment of step c), mixture containing 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine obtained in step b) can be extracted using aromatic hydrocarbon solvent such as toluene, xylene or benzene.
Resulting mixture can be allowed to separate the organic and aqueous layer. Organic layer containing 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine can be treated with acid selected from the group consisting of inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid and resulting mixture can be filtered to remove Impurity-H. Resulting filtrate can be used in step d) to isolate pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine.
In the first embodiment of step d), resulting filtrate containing 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine can be treated with base and layers can be separated. 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III can be isolated from the separated organic layer by removing the solvent. Generally, solvent can be removed by distillation.
In the first embodiment of step d), resulting pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
contain less than 0.1% of dimer Impurity-H,

[Impurity-H].
In the first embodiment of step e), pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III can be reacted with 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV or salt thereof in presence of 4-dimethylaminopyridine and solvent to obtain Trazodone of Formula-I or salt thereof.
In the first embodiment of step e), solvent can be selected from the group comprising of aromatic hydrocarbon solvents such as toluene, benzene, xylene, naphthalene, tetraline; ethers such as diethyl ether, n-propyl ether, di-isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, or dimethoxyethane; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; alcohol such as methanol, ethanol, or isopropanol; dimethylsulfoxide; amide solvents such as dimethyl formamide, dimethyl acetamide, N-methylpyrrolidone; or mixture(s) thereof.
In the first embodiment of step e), reaction of compound of Formula-III with compound of Formula-IV or salt thereof can be carried out at temperature of 60°C reflux temperature of the solvent used, preferably at 90°C to 120°C for a period of 15 hours to 21 hours.
In the first embodiment of step e), salt of compound of Formula-IV can be selected from the group consisting of alkali metal salt such as sodium, potassium, or calcium.
In the first embodiment of step e), molar equivalent of compound of Formula-IV with respect to compound of the Formula-III can be in the range of 1.0 to 1.5.
In the first embodiment of step e), molar equivalent of 4-dimethylaminopyridine with respect to compound of the Formula-III can be in the range of 0.05 to 0.1.
In the first embodiment of step e), after completion of reaction, solvent can be distilled out completely and water can be added to the residual mass followed by further distillation partly till the removal of organic solvent. Water can be added to resulting partly distilled mass followed by cooling at 35oC to 40oC. Resulting solid can be filtered. Resulting solid can be mixed with isopropanol. Activated carbon can be added to the mixture and hot filtered to obtain filtrate. Resulting filtrate can be cooled slowly to 0oC to 10oC to obtain a solid. Resulting Trazodone of Formula-I can be isolated by filtration.
Resulting pure Trazodone of Formula-I can have purity greater than 99%, preferably greater than 99.8% by HPLC (High-performance liquid chromatography).
1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III, defined herein after as Impurity-2,

[Impurity-2]
used as staring material for the preparation of Trazodone is itself genotoxic in nature. Therefore, control of Impurity-2 in final Trazodone API is very important.
In the first embodiment of step e), content of Impurity-2 in Trazodone of Formula-I is below the limit of detection.
According to second embodiment, the present invention provides a process for the preparation of highly pure 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II,

[Formula-II]
comprising reacting 3-chloroaniline with bis-(2-chloroethylamine) hydrochloride in presence of alkali metal hydroxide and water to obtain 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II.
In the second embodiment, alkali metal hydroxide can be selected from the group consisting of sodium hydroxide, potassium hydroxide, or lithium hydroxide.
In the second embodiment, molar equivalent of bis-(2-chloroethylamine) hydrochloride with respect to 3-chloroaniline can be in the range of 1.0 to 1.5.
In the second embodiment, reaction of 3-chloroaniline with bis-(2-chloroethylamine) hydrochloride can be carried out at a temperature of 60°C to 110°C, preferably at 90°C to 110°C for a period of 2 hours to 6 hours.
In the second embodiment, obtained 1-(3-chlorophenyl)piperazine hydrochloride can be treated with base in presence of water at 60°C to 80°C to obtain 1-(3-chlorophenyl)piperazine. Base can be selected from the group consisting of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide. Resulting 1-(3-chlorophenyl)piperazine can be extracted with solvent such as aromatic hydrocarbon solvent for example, benzene, toluene, or xylene and then can be treated with hydrochloric acid to obtain 1-(3-chlorophenyl)piperazine hydrochloride. Hydrochloric acid can be used in the form of solution or in the form of gas. Solution of hydrochloric acid can be concentrated or dilute. Hydrochloric acid (HCl) can also be used in the form of alcoholic solution of hydrochloric acid selected from the group consisting of methanolic HCl, ethanolic HCl, or isopropanolic HCl.
1-(3-chlorophenyl)piperazine hydrochloride can be isolated by technique of isolation methods known in the prior art, such as cooling, crystallization, recrystallization, or solvent-anti solvent methods; preferably by cooling to 0oC to 10°C over a period of 1 hour to 2 hours.
In the second embodiment, content of Impurity-1 in 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II is below the level of detection.
According to third embodiment, the present invention provides a highly pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
containing less than 0.1% of dimer Impurity-H,

[Impurity-H].
According to fourth embodiment, the present invention provides a process for the preparation of highly pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
containing less than 0.1% of dimer Impurity-H,

[Impurity-H]
comprising the steps of:
a) reacting 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II,

[Formula-II]
with 1-bromo-3-chloropropane in presence of base and water to obtain a mixture;
b) treating mixture obtained in step a) with acid in presence of aromatic hydrocarbon solvent;
c) isolating pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
containing less than 0.15% of dimer Impurity-H,

[Impurity-H]
after treatment with base.
In the fourth embodiment of step a), 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II can be reacted with 1-bromo-3-chloropropane in presence of base and water to obtain mixture containing 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine.
In the fourth embodiment of step a), molar equivalent of 1-bromo-3-chloropropane with respect to 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II can be in the range of 1.0 to 1.6.
In the fourth embodiment of step a), base can be selected from the group consisting of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate.
In the fourth embodiment of step a), reaction of 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II with 1-bromo-3-chloropropane can be carried out at a temperature of 20oC to 60oC, preferably at 30oC to 40oC for a period of 15 hours to 20 hours. After completion of reaction, acid can be added to resulting mixture containing 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine to adjust the pH in the range of 8 to 9.
In the fourth embodiment of step b), mixture containing 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine obtained in step a) can be extracted using aromatic hydrocarbon solvent such as toluene, xylene or benzene.
Resulting mixture can be allowed to separate the organic and aqueous layer. Organic layer containing 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine can be treated with acid selected from the group consisting of inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid and resulting mixture can be filtered to remove Impurity-H. Resulting filtrate can be used in step c) to isolate pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine.
In the fourth embodiment of step c), resulting filtrate containing 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine can be treated with base and layers can then be separated. Pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III can then be isolated from the organic layer by removing the solvent. Generally, solvent can be removed by distillation.
In the fourth embodiment of step c), resulting pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
contain less than 0.1% of dimer Impurity-H,

[Impurity-H].
According to fifth embodiment, the present invention provides a process for the preparation of highly pure Trazodone of Formula-I,

[Formula-I]
or salt thereof,
comprising reacting pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
with 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV,

[Formula-IV]
or salt thereof, in presence of 4-dimethylaminopyridine and solvent to obtain pure Trazodone of Formula-I or salt thereof.
In the fifth embodiment, pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III can be reacted with 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV or salt thereof in presence of 4-dimethylaminopyridine and solvent to obtain Trazodone of Formula-I or salt thereof.
In the fifth embodiment, solvent can be selected from the group comprising of aromatic hydrocarbon solvents such as toluene, benzene, xylene, naphthalene, tetraline; ethers such as diethyl ether, n-propyl ether, di-isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, or dimethoxyethane; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; alcohol such as methanol, ethanol, or isopropanol; dimethylsulfoxide; amide solvents such as dimethyl formamide, dimethyl acetamide, N-methylpyrrolidone; or mixture(s) thereof.
In the fifth embodiment, reaction of compound of Formula-III with compound of Formula-IV or salt thereof can be carried out at temperature of 60°C reflux temperature of the solvent used, preferably at 90°C to 120°C for a period of 15 hours to 21 hours.
In the fifth embodiment, salt of compound of Formula-IV can be selected from the group consisting of alkali metal salt such as sodium, potassium, or calcium.
In the fifth embodiment, molar equivalent of compound of Formula-IV with respect to compound of the Formula-III can be in the range of 1.0 to 1.5.
In the fifth embodiment, molar equivalent of 4-dimethylaminopyridine with respect to compound of the Formula-III can be in the range of 0.05 to 0.1.
In the fifth embodiment, after completion of reaction, solvent can be distilled out completely and water can be added to the residual mass followed by further distillation partly till the removal of organic solvent. Water can be added to resulting partly distilled mass followed by cooling at 35oC to 40oC. Resulting solid can be filtered. Resulting solid can be mixed with isopropanol. Activated carbon can be added to the mixture and hot filtered to obtain filtrate. Resulting filtrate can be cooled slowly to 0oC to 10oC to obtain a solid. Resulting Trazodone of Formula-I can be isolated by filtration.
Resulting Trazodone of Formula-I can have purity greater than 99%, preferably greater than 99.8% by HPLC (High-performance liquid chromatography).
1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III (Impurity-2),

[Impurity-2]
used as staring material for the preparation of Trazodone is itself genotoxic in nature. Therefore, control of Impurity-2 in final Trazodone API is very important.
In the fifth embodiment, content of Impurity-2 in Trazodone of Formula-I is below the limit of detection.
According to sixth embodiment, the present invention provides a process for the preparation of highly pure 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV,

[Formula-IV]
or salt thereof comprising reacting 2-chloropyridine with semicarbazide hydrochloride in presence of acid, phase transfer catalyst, and water to obtain 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV or salt thereof.
In the sixth embodiment, acid can be selected from the group consisting of inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid.
In the sixth embodiment, phase transfer catalyst can be selected from the group consisting of tricaprylyl methyl ammonium chloride (Aliquat 336), tetra-n-butyl ammonium bromide (TBAB), triethylbenzylammonium chloride (TEBAC), cetyltrimethylammonium bromide (CTAB), cetylpyridiniumbromide, N-benzylquininiumchloride, tetra-n-butyl ammonium chloride, tetra-n-butyl ammonium hydroxide, tetra-n-butyl ammonium iodide, tetra- ethyl ammonium chloride, benzyltributyl ammonium chloride, benzyltriethylammoniumbromide, hexadecyltriethylammoniumchloride, tetramethylammonium chloride, hexadecyltrimethylammonium chloride and octyltrimethylammoniumchloride or a mixture thereof.
In the sixth embodiment, reaction of 2-chloropyridine with semicarbazide hydrochloride in presence of acid, phase transfer catalyst and water can be carried out at a temperature of 100°C to 145°C, preferably at 120°C to 140°C for a period of 16 hours to 22 hours.
In the sixth embodiment, isolation of 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV, or salt thereof, can be carried out by any technique of isolation known in the art, such as cooling, crystallization, recrystallization, or solvent-anti solvent methods preferably by cooling.
In the sixth embodiment, isolated 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV is having purity greater than 99.7%, preferably greater than 99.9% by HPLC.
According to seventh embodiment, the present invention provides a process for the preparation of highly pure 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II,

[Formula-II]
comprising the steps of:
a) reacting 3-chloroaniline with bis-(2-chloroethylamine) hydrochloride in presence of aromatic hydrocarbon solvent to obtain 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II;

[Formula-II]
b) treating 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II with base in presence of water to obtain 1-(3-chlorophenyl)piperazine;
c) isolating 1-(3-chlorophenyl)piperazine by extraction with aromatic hydrocarbon solvent;
d) treating 1-(3-chlorophenyl)piperazine with hydrochloric acid in presence of aromatic hydrocarbon solvent to obtain highly pure 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II,

[Formula-II].
In the seventh embodiment of step a), aromatic hydrocarbon solvent can be selected from the group consisting of benzene, xylene or toluene.
In the seventh embodiment of step a), reaction of 3-chloroaniline with bis-(2-chloroethylamine) hydrochloride in presence of aromatic hydrocarbon solvent can be carried out at a temperature of 80oC to a reflux temperature of solvent, preferably at 140°C to 150°C for a period of 25 hours to 30 hours.
In the seventh embodiment of step b), obtained 1-(3-chlorophenyl)piperazine hydrochloride can be treated with base in presence of water at 60°C to 80°C to obtain 1-(3-chlorophenyl)piperazine. Base can be selected from the group consisting of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide.
In the seventh embodiment of step c), resulting 1-(3-chlorophenyl)piperazine can be extracted with solvent such as aromatic hydrocarbon solvent for example, benzene, toluene, or xylene
In the seventh embodiment of step d), 1-(3-chlorophenyl)piperazine can be treated with hydrochloric acid to obtain 1-(3-chlorophenyl)piperazine hydrochloride. Hydrochloric acid can be used in the form of solution or in the form of gas. Solution of hydrochloric acid can be concentrated or dilute. Hydrochloric acid (HCl) can also be used in the form of alcoholic solution of hydrochloric acid selected from the group consisting of methanolic HCl, ethanolic HCl, or isopropanolic HCl.
1-(3-chlorophenyl)piperazine hydrochloride can be isolated by technique of isolation methods known in the prior art, such as cooling, crystallization, recrystallization, or solvent-anti solvent methods; preferably by cooling to 0oC to 10°C over a period of 1 hour to 2 hours.
In the seventh embodiment of step d), content of bis-(2-chloroethylamine) hydrochloride (Impurity-1) in 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II is below the level of detection.
Resulting 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II can have purity greater than 99.0%, preferably more than 99.9% by HPLC.
According to eighth embodiment, the present invention provides a process for the preparation of highly pure Trazodone hydrochloride of Formula-V,

[Formula-V]
comprising the steps of:
a) dissolving Trazodone of Formula-I,

[Formula-I]
in isopropyl alcohol;
b) adding hydrochloric acid to solution obtained in step a);
c) isolating Trazodone hydrochloride of Formula-V.
In the eighth embodiment of step a), Trazodone of Formula-I can be dissolved in isopropyl alcohol by heating to a temperature of 40°C to 80°C, preferably at 60°C to 65°C.
In the eighth embodiment of step b), hydrochloric acid may be used in the form of solution or may be used in the form of gas. Solution of hydrochloric acid can be concentrated or dilute.
In the eighth embodiment of step c), isolation of Trazodone hydrochloride of Formula-V can be carried out by any technique of isolation known in the art such as cooling, crystallization, recrystallization, or solvent-anti solvent methods or combination thereof; preferably by addition of water and stepwise cooling.
In the eighth embodiment of step c), Trazodone hydrochloride of Formula-V can have purity greater than 99%, preferably greater than 99.8% by HPLC.
European Pharmacopoeia monographs of Trazodone hydrochloride discloses various impurities of Trazodone Hydrochloride, namely, Impurity-A, Impurity-B, Impurity-C, Impurity-D, Impurity-E, Impurity-G, Impurity-H, Impurity-I, Impurity-J, Impurity-K, Impurity-L, Impurity-M.
Trazodone hydrochloride obtained according to present invention controls these impurities as mentioned in Table-1.
Table-1: Impurity profile of Trazodone hydrochloride of Formula-V
Name of impurity Structure Impurity content (%)
Impurity-A
Not detected
Impurity-B

Not detected
Impurity-C
Not detected
Impurity-D
0.05
Impurity-E
Not detected
Impurity-G
Not detected
Impurity-H
Not detected
Impurity-I
Not detected
Impurity-J
Not detected
Impurity-K
Not detected
Impurity-L
Not detected
Impurity-M
Not detected
In the eighth embodiment of step c), content of genotoxic impurities namely Impurity-1, Impurity-2 and Impurity-3 in Trazodone hydrochloride of Formula-V is less than 1 ppm (parts per million).
Trazodone hydrochloride obtained according to present invention controls these impurities as mentioned in Table-2.
Table-2: Content of genotoxic impurities in Trazodone hydrochloride of Formula-V
Name of impurity Structure Impurity content
(ppm)
Impurity-1
0.58
Impurity-2
Not detected
Impurity-3
Not detected

According to ninth embodiment, the present invention provides crystalline form AL-1 of Trazodone characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-1.
In the ninth embodiment, crystalline form AL-1 of Trazodone can be characterized by X-ray powder diffraction (XRPD) pattern comprising peaks at 5.6, 12.5, 17.6 and 17.8 ± 0.2° 2?.
According to tenth embodiment, the present invention provides crystalline form AL-2 of Trazodone hydrochloride characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-2 and Differential scanning calorimetry (DSC) chromatograph as shown in Figure-3.
In the tenth embodiment, crystalline form AL-2 of Trazodone hydrochloride can be characterized by X-ray powder diffraction (XRPD) pattern comprising peaks at 5.2, 10.5, 17.8, 23.0, and 23.6± 0.2° 2?.
In the tenth embodiment, crystalline form AL-2 of Trazodone hydrochloride can be further characterized by X-ray powder diffraction (XRPD) pattern comprising peaks at 19.2, 21.0, 21.7, and 24.4± 0.2° 2?.
In the tenth embodiment, crystalline form AL-2 of Trazodone hydrochloride can be characterized by Differential scanning calorimetry (DSC) comprising characteristic peak at 233.84oC.
EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.
Example 01: Preparation of 1-(3-chlorophenyl)piperazine hydrochloride
To a stirred mixture of 3-chloro aniline (100 g) and water (150 mL), bis-(2-chloroethylamine) hydrochloride (154 g) was added at 25°C to 35°C. Resulting mixture was heated at 100°C to 110°C and aqueous sodium hydroxide solution (sodium hydroxide (66.8 g) + purified water (75 mL) was added to the mixture at the same temperature. Resulting mixture was stirred at 100°C to 110°C for 4 hours. After completion of reaction, mixture was cooled to 60°C to 70°C and purified water (500 mL) was added. Caustic soda lye (60 mL) and toluene (400 mL) were added into the resulting mixture at the same temperature. Resulting mixture was stirred and allowed layers to separate. The aqueous layer was washed with toluene (200 mL). Combined all the organic layer and washed with 3% aqueous sodium chloride solution (200 mL) at 60°C to 70°C. Resulting organic layer was filtered, washed with toluene (100 mL), and filtrate was distilled to remove the solvent. Isopropyl alcohol (157 mL) and isopropyl alcohol hydrochloride (157 g) were added to the obtained distilled mass and resulting mixture was heated to 80°C to 85°C and stirred for 35 minutes. Mixture was cooled to 25°C to 35°C and further cooled to 0°C to 10°C. Resulting mixture was stirred for 1.5 hour at the same temperature and filtered to obtain a solid. Resulting solid was dried at 60°C to 65°C for a period of 8 hours to obtain a title compound.
Yield: 113.3 g; Purity: 99.95% (by HPLC); % of Impurity-1: Not detected
Example 02: Preparation of 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine
To a stirred mixture of caustic soda flakes (128.7 g) and water (900 mL), 1-(3-chlorophenyl)piperazine hydrochloride (300 g) and 1-bromo-3-chloropropane (304.07 g) were added at 25°C to 35°C. Resulting mixture was heated to 30°C to 40°C and stirred at the same temperature for 18 hours. After completion of reaction, resulting mixture was cooled to 25°C to 35°C. Aqueous hydrochloric acid solution (1:1) was added into the resulting mixture and pH was adjusted to 8.5. Toluene (1200 mL) was added into the mixture at 25°C to 35°C. Resulting mixture was stirred and allowed layers to separate. Resulting aqueous layer was extracted with toluene (300 mL). All the organic layers were combined, and hydrochloric acid (12.0 g) was added. Resulting mixture was filtered and sodium hydroxide solution (30 g caustic soda flakes in 600 mL water) was added into the obtained filtrate. Resulting mixture was stirred and allowed layers to separate. Resulting organic layer was treated with activated carbon (7.5 g) and filtered. Resulting filtrate was distilled to obtain a title compound.
Yield: 310 g; Purity: 99.47% (by HPLC); % of dimer Impurity-H: 0.03%
Example 03: Preparation of 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one
To a stirred mixture of 2-chloropyridine (300 g) and water (150 mL), semicarbazide hydrochloride (648 g) was added at 25°C to 35°C. Sulphuric acid (7.5 g) and tetra butyl ammonium bromide (0.15 g) were added into the resulting mixture at the same temperature and mixture was heated to 125°C to 135°C. Resulting mixture was stirred at 125°C to 135°C for 20 hours. After completion of reaction, mixture was cooled to 80°C to 90°C and water (900 mL) was added. Resulting mixture was cooled to 20°C to 30°C. Resulting mixture was filtered, washed with water (300 mL) and dried at 70°C to 75°C for a period of 8 hours to obtain a title compound.
Yield: 275 gm; Purity: 99.92% (by HPLC)
Example 04: Preparation of sodium salt of 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one
To a stirred mixture of caustic soda flakes (88.5 g) and water (500 mL), [1,2,4]triazolo[4,3-a] pyridin-3(2H)-one (250 g) was added at 25°C to 35°C. Resulting mixture was heated to 80°C to 85°C and stirred for 1 hour. After completion of reaction, mixture was cooled to 25°C to 35°C and water (250 mL) was added. The resulting mixture was further cooled to 5°C to 10°C and stirred for 1 hour. Resulting mixture was filtered, washed with water (187 mL) and dried under vacuum at 70°C to 75°C for a period of 24 hours to obtain a title compound.
Yield: 265 g; Purity: 99.99% (by HPLC)
Example 05: Preparation of Trazodone
To a stirred mixture of toluene (1000 mL) and 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (250 g), sodium 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (165 g) and 4-dimethyl amino pyridine (7.5 g) were added at 25°C to 35°C. Resulting mixture was heated to 105°C to 115°C and stirred at the same temperature for 18 hours. After completion of reaction, mixture was cooled to 60°C to 65°C and resulting mixture was distilled under vacuum to remove solvent. Water (500 mL) was added into the obtained residual mass at a temperature below 65°C and resulting mixture was distilled under vacuum at the same temperature. Water (750 mL) was added into the residual mass and mixture was stirred for 15 minutes. Resulting mixture was cooled to 35°C to 40°C and filtered to obtain a solid. Resulting solid was washed with water (250 mL), dried and dissolved in isopropyl alcohol (1000 mL) by heating to temperature of 60°C to 65°C. Activated carbon slurry (activated carbon (6.25 g) in isopropyl alcohol (250 mL)) was added into the resulting solution and solution was heated to temperature of 70°C to 75°C. Resulting solution was filtered and obtained filtrate was cooled to 45°C to 50°C and further cooled to 0°C to 10°C. Resulting mixture was filtered and again treated with isopropyl alcohol, filtered, washed with isopropyl alcohol and dried under vacuum at 55°C to 60°C for a period of 8 hours to obtain a title compound.
Yield: 245.9 g; Purity: 99.85% (by HPLC); % of Impurity-2: Not detected
Example 06: Preparation of Trazodone hydrochloride
Trazodone (230 g) was added into isopropyl alcohol (690 mL). Resulting solution was heated to 60°C to 65°C and activated carbon slurry (5.75 g activated carbon in 115 mL isopropyl alcohol) was added. Resulting mixture was filtered and washed with isopropyl alcohol (115 mL). Hydrochloric acid (95.22 g) was added into the obtained filtrate at 60°C to 65°C and resulting mixture was heated to 80°C to 85°C. Water (40 mL) was added into the resulting mixture and mixture was stirred for 15 minutes at 80°C to 85°C. Resulting mixture was gradually cooled to 0°C to 10°C and filtered at the same temperature. Resulting precipitate was recrystallised from isopropyl alcohol to obtain a title compound.
Yield: 181 g; Purity: 99.84% (by HPLC) [Content of impurities are as mentioned in Table-1 and Table-2]
Example 07: Preparation of 1-(3-chlorophenyl)piperazine hydrochloride
To a stirred mixture of 3-Chloro aniline (300 g) and o-xylene (900 mL), bis-(2-chloroethylamine) hydrochloride (440.8 g) was added at 25°C to 35°C and mixture was heated to 140°C to 145°C. Resulting mixture was maintained at the same temperature for 30 hours. After completion of reaction, mixture was cooled to 25°C to 35°C, further cooled to 0°C to 10°C and filtered at the same temperature. Resulting precipitate was added into the mixture of Caustic soda flakes (282 g) and water (1350 mL) at 25°C to 35°C and stirred for 15 minutes. To the resulting mixture, toluene (900 mL) was added, and mixture was stirred for 30 minutes at the same temperature and allowed layers to separate. Resulting aqueous layer was extracted with toluene (300 mL) and allowed layers to separate. The organic layers were combined and distilled to remove solvent. Obtained residual mass was distilled under high vacuum (0.1-0.5 mm/Hg) to get the product oil. To a stirred mixture of obtained residual mass and toluene (1500 mL), isopropyl alcohol hydrochloride (390 g) was added at 25°C to 35°C and mixture was cooled to 0°C to 10°C. Resulting mixture was stirred for 90 minutes at the same temperature and filtered to obtain a solid. Resulting solid was dried at 60°C to 65°C for a period of 8 hours to obtain a title compound.
Yield: 352 g; Purity: 99.83% (by HPLC); % of Impurity-1: Not detected

,CLAIMS:I / We Claim:
1. A process for the preparation of highly pure Trazodone of Formula-I,

[Formula-I]
or salt thereof, comprising the steps of:
a) reacting 3-chloroaniline with bis-(2-chloroethylamine) hydrochloride in presence of alkali metal hydroxide and water to obtain 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II;

[Formula-II]
b) reacting 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II with 1-bromo-3-chloropropane in presence of base and water to obtain a mixture;
c) treating mixture obtained in step b) with acid in presence of aromatic hydrocarbon solvent;
d) isolating pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
containing less than 0.1% of dimer Impurity-H,

[Impurity-H]
after treatment with base;
e) reacting pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III
with 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV,

[Formula-IV]
or salt thereof in presence of 4-dimethylaminopyridine and solvent to obtain highly pure Trazodone of Formula-I or salt thereof.
2. The process as claimed in claim 1, wherein alkali metal hydroxide of step a) is sodium hydroxide, potassium hydroxide, or lithium hydroxide; base of step b) is alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; aromatic hydrocarbon solvent of step c) is toluene, xylene or benzene.
3. A process for the preparation of highly pure 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II,

[Formula-II]

comprising reacting 3-chloroaniline with bis-(2-chloroethylamine) hydrochloride in presence of alkali metal hydroxide and water to obtain 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II.
4. The process as claimed in claim 3, wherein reaction of 3-chloroaniline with bis-(2-chloroethylamine) hydrochloride can be carried out using alkali metal hydroxide selected from the sodium hydroxide, potassium hydroxide, or lithium hydroxide and water at temperature of 60°C to 110°C
5. A highly pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
containing less than 0.1% of dimer Impurity-H,

[Impurity-H].
6. A process for the preparation of highly pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
containing less than 0.1% of dimer Impurity-H,

[Impurity-H]
comprising the steps of:
a) reacting 1-(3-chlorophenyl)piperazine hydrochloride of Formula-II,

[Formula-II]
with 1-bromo-3-chloropropane in presence of base and water to obtain a mixture;
b) treating mixture obtained in step a) with acid in presence of aromatic hydrocarbon solvent;
c) isolating pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
containing less than 0.15% of dimer Impurity-H,

[Impurity-H]
after treatment with base.
7. A process for the preparation of highly pure Trazodone of Formula-I,

[Formula-I]
or salt thereof,
comprising reacting pure 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of Formula-III,

[Formula-III]
with 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV,

[Formula-IV]
or salt thereof, in presence of 4-dimethylaminopyridine and solvent to obtain pure Trazodone of Formula-I or salt thereof.
8. A process for the preparation of highly pure 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV,

[Formula-IV]
or salt thereof comprising reacting 2-chloropyridine with semicarbazide hydrochloride in presence of acid, phase transfer catalyst, and water to obtain 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one of Formula-IV or salt thereof.
9. A process for the preparation of highly pure Trazodone hydrochloride of Formula-V,

[Formula-V]
comprising the steps of:
a) dissolving Trazodone of Formula-I,

[Formula-I]
in isopropyl alcohol;
b) adding hydrochloric acid to solution obtained in step a);
c) isolating Trazodone hydrochloride of Formula-V.
10. Trazodone hydrochloride devoid of impurities namely Impurity-A, B, C, E, G, H, I, J, K, L, M, Impurity-1, Impurity-2, Impurity-3

Impurity-A
Impurity-H
Impurity-M

Impurity-B
Impurity-I
Impurity-1

Impurity-C

Impurity-J
Impurity-2

Impurity-E

Impurity-K
Impurity-3

Impurity-G
Impurity-L

Dated this 10th October 2024

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.