Description:FIELD OF THE INVENTION
The present invention relates to the field of pharmaceuticals, more specifically, to a novel process for the preparation of Trazodone hydrochloride (Formula -1), a compound widely used in the treatment of various psychological conditions.
BACKGROUND OF THE INVENTION
Trazodone hydrochloride is an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) class. It is chemically known as 2-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo [4, 3-a]pyridin-3(2H)-one hydrochloride.
Since its discovery, Trazodone hydrochloride has been extensively used for its antidepressant, anxiolytic, and hypnotic properties. It is commonly prescribed for the treatment of depression with or without accompanying anxiety, insomnia related to stress and depression, and for the control of various behavioural symptoms in patients with neurological conditions.
The therapeutic benefits of Trazodone, coupled with its relatively mild side-effect profile compared to other antidepressants, have made it a valuable tool in the psychiatric and psychological treatment arsenal. Its mechanism of action primarily involves the modulation of serotonin activity in the brain, contributing to its effectiveness in improving mood, anxiety symptoms, and sleep patterns.
Trazodone is available for medical use since 1981.
Molecular Structure of Trazodone hydrochloride is represented herein below: -

IUPAC Name:- 2-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo
[4, 3-a]pyridin-3(2H)-one hydrochloride.
The synthesis of Trazodone hydrochloride, as documented in existing literature and patents, involves complex chemical processes that present several operational and environmental challenges. Notably, the existing art in the preparation of Trazodone hydrochloride, including patents EP2178850B1, US 3381009, WO2009019133, US8133893, and US8314236, outlines methods for preparing Trazodone base using 1,2,4-trizolo(4,3-a)pyridine-3-(2H)-one and 1-(3-Chlorophenyl)-4-(3-chloropropyl) piperazine in dioxane in the presence of sodium hydride. These patents also describe the purification of Trazodone base through dissolution in organic solvents selected from the group comprising alcohols, ethers, hydrocarbons, ketone and ester; and subsequent treatment with an aqueous phase containing an inorganic or organic base; followed by separation of phases and isolation of Trazodone base free from alkylation impurities, dissolving the said base in acetone; and then conversion of Trazodone base to Trazodone hydrochloride through treatment with hydrochloric acid.
Additional methodologies are presented in patents EP3749668, US2021032243, and BR1120200158555, which detail manufacturing processes for Trazodone as a free base, including the use of flow reactors and alkaline aqueous solutions for reaction facilitation. Patent PL234822B1 describes the preparation of Trazodone via the reaction of specific chemical intermediates in the presence of potassium carbonate and phase transfer catalysts, employing microwave radiation for reaction enhancement. Similarly, IN392264 outlines a method for producing Trazodone hydrochloride by reacting 1-(3-Chloropropyl)-4-(3-Chlorophenyl)piperazine with the sodium salt of 1,2,4-trizolo(4,3-a) pyridine-3(2H)-one, utilizing a phase transfer catalyst.
Despite the advancements documented in these patents, the current methodologies for synthesizing Trazodone hydrochloride exhibit several limitations:
1. Purification of Trazodone Base: Current methods necessitate the purification of Trazodone base, a step that introduces additional complexity and cost to the production process. This requirement for purification not only extends the time needed to produce Trazodone hydrochloride but also increases the risk of impurities and variability in the final product quality. Also it requires use of organic solvents which are hazardous of environment.
2. Use of Catalyst for Condensation: The synthesis of Trazodone hydrochloride typically involves the condensation of 1-(3-Chloropropyl)-4-(3-Chlorophenyl)piperazine and sodium 1,2,4-trizolo (4,3-a) pyridine-3(2H)-one. This step requires the use of catalysts, which can pose environmental and safety concerns. The disposal of catalysts and the management of catalytic residues can contribute to the overall environmental footprint of the production process.
3. Use of Microwave Radiation for Condensation: The condensation step often employs microwave radiation to facilitate the reaction. While effective in promoting the desired chemical transformations, the use of microwave radiation necessitates specialized equipment and can raise concerns regarding energy consumption and operational, environmental and health safety.
OBJECTS OF THE INVENTION
One of the objects of the invention is to provide an improved method for the synthesis of Trazodone hydrochloride that eliminates the necessity for purification of the Trazodone base and reducing the reliance on hazardous catalysts and microwave radiation and promote the lesser use of organic solvent inter alia “Green Chemistry”.
Another object of the invention is to enhance the environmental sustainability of the Trazodone hydrochloride synthesis process through the selective use of solvents and reagents, aiming to minimize the environmental impact and promote a greener manufacturing approach.
Yet another object of the invention is to improve the yield and purity of Trazodone hydrochloride, ensuring that the final product not only meets but exceeds pharmacopeial standards for quality, thus enhancing its therapeutic efficacy and safety.
Yet another object of the invention is to reduce the production costs associated with the manufacturing of Trazodone hydrochloride. By optimizing the synthesis process and minimizing the use of costly reagents and extensive purification steps, the invention seeks to make the production more cost-effective.
A further object of the invention is to safeguard against the presence of genotoxic impurities, such as 1-(3-Chlorophenyl)-4-(3-chloropropyl)piperazine and others, within Trazodone hydrochloride. The method meticulously controls reaction conditions and stoichiometry to ensure that genotoxic impurities are kept well within the acceptable limits, thereby ensuring the safety of the final pharmaceutical product.
Still another object of the invention is to achieve a higher degree of control and precision in the reaction conditions, including temperature and reaction duration. This precision allows for a more efficient reaction pathway, further contributing to the yield, purity, and cost-effectiveness of the process.
Lastly, an object of the invention is to demonstrate the versatility of the synthesis method in accommodating various solvents and conditions, thereby providing a robust and flexible approach to the production of Trazodone hydrochloride that can be adapted to different manufacturing settings and requirements.

SUMMARY OF THE INVENTION
The present invention relates to a process for preparation of Trazodone hydrochloride of formula-I.

(Formula -1)

Comprising of following reaction scheme-

(I) (II)


(II) (III) (IV)

(IV) (Formula -1)

The above reaction scheme involves:

Step 1: This step involves generation of the sodium salt of 1,2,4-trizolo (4,3-a) pyridine-3(2H)-one. This is achieved by treating 1,2,4-trizolo (4,3-a) pyridine-3(2H)-one with an aqueous alkali solution in the presence of isopropanol, setting the foundation for subsequent reaction stages.

Step 2: Following the formation of sodium salt of 1,2,4-trizolo (4,3-a) pyridine-3(2H)-one, it is then reacted with 1-(3-Chloropropyl)-4-(3-Chlorophenyl)piperazine hydrochloride. This step is facilitated by the use of alcohols as solvents, including methanol, ethanol, n-propanol, and isopropanol, with isopropanol being the preferred choice. The outcome of this reaction is the formation of Trazodone base, marking a critical intermediate step in the synthesis.

Step 3: The Trazodone base thus obtained is then subjected to charcoal treatment involving dissolution in an alcohol, such as methanol. The solution is treated with activated charcoal and filtered to achieve a clear solution, effectively enhancing the colour of Trazodone base in solution.

Step 4: In the final step, the purified Trazodone base solution in methanol is treated with an isopropyl alcohol-hydrochloric acid (IPA-HCl) solution. This crucial step results in the formation of Trazodone hydrochloride, completing the synthesis process.

This present invention provides a streamlined, straightforward and simplified method for synthesis of Trazodone hydrochloride, characterized by low production costs, high yield and superior quality of the final product, Trazodone hydrochloride. Furthermore, the method is environment friendly minimizing the ecological impact and promoting sustainability in manufacturing process.

DETAILED DESCRIPTION OF THE INVENTION
The inventors of the present invention have identified that previous methods for synthesizing Trazodone hydrochloride often necessitated the use of catalysts, involved complex purification steps for the Trazodone base, and relied on microwave radiation. In contrast, the method presented herein utilizes a specific solvent system that not only simplifies the synthesis but also ensures the final product meets all relevant Pharmacopoeia standards. A significant advantage of this method is its meticulous management of genotoxic impurities, which include but are not limited to, 1-(3-Chlorophenyl)-4-(3-chloropropyl) piperazine, Bis-(2-Chloroethyl)amine, hydrazine hydrate, 1-Bromo-3-chloropropane, 4-(3-Chlorophenyl)-1-(3-bromopropyl)piperazine hydrochloride, and 1-(3,4-Dichlorophenyl)-4-(3-chloropropyl) piperazine.
The detailed method involved in preparation of Trazodone hydrochloride is provided herein below:
1. N-alkylation Reaction: This initial step involves the N-alkylation of sodium 1,2,4-trizolo(4,3-a)pyridine-3-(2H)-one with 1-(3-Chlorophenyl)-4-(3-chloropropyl) piperazine hydrochloride, employing a range of alcohols (methanol, ethanol, n-propanol, isopropanol, butanol, Isobutanol, or their mixtures) as solvents. The preferred solvent for this reaction is isopropanol. The N-alkylation is efficiently conducted at temperatures ranging from 60°C to 100°C, with an optimal temperature window of 78-85°C. Following the reaction, the product is isolated through cooling, filtration, washing, and drying, adhering to the depicted reaction scheme.
The reaction scheme is represented by following equation:-

2. Conversion to Hydrochloride Salt: In the subsequent step, the dried Trazodone base undergoes conversion to its hydrochloride salt form. This involves dissolving the Trazodone base in an alcohol, preferably methanol, followed by charcoal treatment and filtration to achieve a clear solution. The filtered solution is then treated with hydrogen chloride dissolved in an alcohol, preferably IPA-HCl, to form Trazodone hydrochloride. The resultant compound is cooled, filtered, washed, and dried, culminating in the acquisition of Trazodone hydrochloride.
The reaction stoichiometry between sodium salt of 1-(3-Chloropropyl)-4-(3-Chlorophenyl) piperazine hydrochloride and sodium 1,2,4-trizolo (4,3-a) pyridine-3(2H)-one is set in such a ratio that any genotoxic impurities are kept well within the acceptable limits set by pharmaceutical compendia, underscoring the method's adherence to safety and quality standards.
The reaction scheme is represented by following equation:-

The Trazodone hydrochloride produced via the present invention exhibits a purity level exceeding 99.5%, with a preference for purity levels greater than 99.9% at commercial scale.
Importantly, the process effectively limits the presence of genotoxic impurities to levels that comply with stringent pharmacopeia standards.
Examples
The following examples are provided to enhance the understanding of the invention. They are intended to be illustrative rather than limiting. Modifications to reaction conditions, such as temperature, reaction duration, or combinations thereof, are envisaged within the scope of this invention. The starting materials used in these examples are either commercially available or can be synthesized by methods known to those skilled in the art.
Example I: Preparation of Trazodone Hydrochloride
Step I: Preparation of Sodium 1,2,4-trizolo (4,3-a) Pyridine-3(2H)-one
1,2,4-trizolo(4,3-a) pyridine-3(2H)-one (300 g, 2.22 moles) was dissolved in an aqueous alkali solution (91.5 g of NaOH in 400 mL water). Upon achieving a homogenous solution, 700mL isopropyl alcohol was added, inducing precipitation of the desired product. The precipitate was collected by centrifugation, washed with 100mL isopropyl alcohol, and dried at 70°C to obtain the sodium salt of the compound (315 g, yield: 89.7%, HPLC 99.91 %).
Step II: Preparation of Trazodone Base
A mixture of 1-(3-Chloropropyl)-4-(3-Chlorophenyl)piperazine hydrochloride (506.3 g, 1.63 moles) in isopropyl alcohol (2700 mL) was treated with potassium carbonate (219 g, 1.586 moles) at room temperature. To this mixture, sodium 1,2,4-trizolo (4,3-a) pyridine-3(2H)-one (250 g, 1.58 moles) was added, and the reaction mixture was stirred for 45±5 minutes. The mixture was then refluxed to complete the reaction. After completion, the reaction mass was filtered and washed with isopropyl alcohol (250 mL). The filtrate was cooled, and the precipitated product was collected by centrifugation, washed with isopropyl alcohol (250 mL), and dried, yielding Trazodone base (525 g, yield: 89.3%, HPLC purity 99.88%).
Step III: Preparation of Trazodone Hydrochloride
Trazodone base (450 g, 1.21 moles) was dissolved in methanol (1825 mL) at a temperature of 40-45°C. The solution was then treated with activated carbon (5 g) and filtered through a hyflow bed to achieve clarity. The filtrate was subsequently treated with an isopropyl alcohol-hydrogen chloride solution (310 g, 20-25% strength) to precipitate Trazodone hydrochloride. The precipitate was collected by centrifugation, washed with a mixture of methanol (25 mL) and isopropyl alcohol (150 mL), and dried to yield the title compound (455 g, yield: 92.0%, HPLC purity 99.8%).
Characterization of Trazodone Hydrochloride Prepared by the method of Present Invention
The Trazodone hydrochloride synthesized by the method of the present invention was rigorously characterized to confirm its chemical structure and to ensure its comparability with the pharmacopoeial reference standard. The analytical techniques employed include Liquid Chromatography-Mass Spectrometry (LCMS), Nuclear Magnetic Resonance (NMR) spectroscopy, Infra-Red (IR) spectroscopy, UV-Visible (UV-Vis) spectroscopy, and X-Ray Diffraction (XRD) crystallography. These methodologies provided a comprehensive analysis, comparing the synthesized Trazodone hydrochloride against an authentic compendial reference standard, USP RS Lot No. HOI132.
Infra-Red (IR) Spectrum:
The IR spectra for the Trazodone hydrochloride prepared by the method of the present invention and the reference standard were recorded. The observed absorption values are in line with the theoretical values reported in the literature, demonstrating the structural integrity of the synthesized product.

[In the above table Trazodone hydrochloride prepared by the method of the present invention is represented by batch sample TZH/402/21-22]
The congruence of the IR spectra between the sample and the reference standard substantiates the structural accuracy of Trazodone hydrochloride synthesized by the present invention.
Nuclear Magnetic Resonance Spectra (NMR):
1H and 13C NMR spectra provided detailed insights into the molecular structure of the synthesized Trazodone hydrochloride. Recorded at different frequencies for the reference standard and the synthesized sample, the chemical shift assignments for protons and carbons were meticulously compared.
NMR 1H Spectrum Table:

NMR 13C Spectrum Table:

[In both the above tables Trazodone hydrochloride prepared by the method of the present invention is represented by batch sample TZH/402/21-22]
Minor variations notwithstanding, the chemical shifts observed in both the tables, for both the reference standard and the Trazodone hydrochloride prepared by the method of the present invention align with the theoretical values, further validating the chemical structure of the Trazodone hydrochloride prepared by the method of the present invention.
Mass Spectrum:
Mass spectrometric analysis was employed to compare the synthesized Trazodone hydrochloride with the reference standard. The mass-to-charge ratio (m/z) of the parent ions was closely examined, indicating a high degree of similarity between the sample and the standard.

[In the above table Trazodone hydrochloride prepared by the method of the present invention is represented by batch sample TZH/402/21-22]
The mass spectrum analysis corroborates the structural similarity of the synthesized Trazodone hydrochloride to the reference standard, affirming its molecular identity.
UV-Visible Spectroscopy:
The UV-Vis spectroscopy analysis of a 0.0025% w/v Trazodone hydrochloride solution revealed an absorption maxima at 246.1 nm, consistent with the reference standard.
The same is represented in following table:

This compliance with the standard absorbance maxima further attests to the quality and purity of the synthesized Trazodone hydrochloride by the method of the present invention.
X-ray Diffraction:
XRD analysis was conducted to determine the crystallinity and polymorphic forms of Trazodone hydrochloride. Three batch samples of the synthesized product were compared, showing no evidence of polymorphism and demonstrating similar crystalline structures.

The consistency in the XRD patterns across different batches emphasizes the reproducibility and reliability of the synthesis process detailed in this invention.

Analysis of Genotoxic impurities in Trazadone hydrochloride prepared by the method of the present invention.

[In the table, “ND” means not detected; Limit of Quantification (LOQ) is the lowest possible concentration of the analyte that can be quantified by the method in a reliable way; Limit of Detection (LOD) is the lowest possible concentration at which the method can detect the analyte in a reliable way] , Claims:We claim:
1. A method for preparing Trazodone hydrochloride of formula-I:
,
(Formula-1),
Comprising of the steps:
(a): Reacting 1,2,4-triazolo (4,3a) pyridine-3(2H)-one with an aqueous alkali solution to form sodium salt of 1,2,4-triazolo (4,3a) pyridine-3(2H)-one,
the step is represented by:

(I) (II) ;
(b): Conducting an N-alkylation reaction of sodium salt of 1,2,4-triazolo (4,3-a) pyridine-3(2H)-one from step (a) with 1-(3-Chlorophenyl)-4-(3-Chloropropyl)piperazine hydrochloride in the presence of an alcohol solvent to produce Trazodone base, the step is represented by:

(II) (III) (IV) ;
;(c): Dissolving the Trazodone base in an alcohol and treating the same with activated carbon to reduce coloration to obtain a purified solution of Trazodone base;
(d): Precipitating Trazodone hydrochloride from the purified solution by treatment with an alcohol-hydrogen chloride solution, wherein the process results in Trazodone hydrochloride, the step is represented by:

(IV) (Formula-1).
2. The method as claimed in claim 1, wherein the aqueous alkali solution comprises sodium hydroxide (NaOH) in water.
3. The method as claimed in claim 1, wherein the alcohol solvent used in step (b) is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, butanol, and isobutanol, or a mixture thereof.
4. The method as claimed in claim 3, wherein isopropanol is the preferred alcohol solvent for conducting the N-alkylation reaction.
5. The method as claimed in claim 1, wherein the N-alkylation reaction is carried out at a temperature range of 60-100°C.
6. The method as claimed in claim 5, wherein the preferred temperature range for the N-alkylation reaction is 78-85°C.
7. The method as claimed in claim 1, wherein the step (c) involves charcoal treatment followed by filtration to obtain a clear solution.
8. The method as claimed in claim 1, further comprising isolating the Trazodone base by cooling, filtration, washing, and drying prior to step (c).
9. The method as claimed in claim 1, wherein the alcohol-hydrogen chloride solution used in step (d) is an isopropyl alcohol-hydrogen chloride (IPA-HCl) solution.
10. The method as claimed in claim 1, wherein the Trazodone hydrochloride produced has a purity greater than 99.5%.
11. The method as claimed in claim 1, wherein the Trazodone hydrochloride produced has a purity greater than 99.9%.
12. The method as claimed in claim 1, wherein the reaction stoichiometry is controlled to ensure that genotoxic impurities are within pharmacopeial standards.