FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification [See Sections 10 and rule 13]
Title: Process For Preparation Of Trazodone And Novel Intermediates
Applicant: (a) INT AS Pharmaceuticals Limited
(b) Company Registered under Indian Company ACT
(c) 2nd Floor, Chinubhai Centre, Ashram Road, Ahmedabad 380009 Gujarat, India
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to preparation of trazodone and its pharmaceutically acceptable salts specifically trazodone hydrochloride.
BACKGROUND OF THE INVENTION
Trazodone chemically known as 2-(3-[4-(3-chlorophenyl)piperazin-l-yl]propyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, is an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) class. It is a phenylpiperazine compound. Trazodone also has anxiolytic and hypnotic effects. Trazodone is also proved effective in controlling pronounced essential tremor, probably on account of its serotonin ranging activity.
Trazodone is preferably used as its hydrochloride salt which can be represented as following formula (II)

Trazodone and process for its preparation is disclosed in US 3,381,009, EP 1108722, US 2010/0056539, WO 2009/019133, WO 2009/105604 and J. Chem. Pharma. Res., 2010, 2(1): 458-472.
One of the processes disclosed in US 3,381,009 is represented as follow:


The process includes use of chloro / bromo propane as an alkylating substance for N-alkylation of compound of formula (III) and then reacting resulting compound of formula (V) with triazole pyridine (VI) in presence of sodium hydride followed by addition of ethereal hydrochloride to give trazodone hydrochloride of formula (II). The process of FR 1117068 discloses use of sodium salt of compound of formula (VI) in preparation of trazodone.
A process to control the particle size of trazodone is disclosed in EP 1108722. The processes reported in prior art uses chloro bromopropane, chloropropyl morpholine or similar alkylating substances for alkylation of l-(3-chlorophenyl)piperazine of formula (III), this results into halogenated alkylating substances such as compound of formula (V) or similar compounds; these compounds when reacted with triazole pyridine (VI) gives trazodone.
The process disclosed in J. Chem. Res. 2010, 2(l):458-472 includes reaction of bis-(2-chloroethylamine) hydrochloride; 3-chloroaniline, para-tolenesulphonic acid to obtain l-(3-chlorophenyl)-piperazine hydrochloride which is reacted with 1-bromo-3-chloro propane and the resultant intermediate is reacted with sodium salt of 1,2,4-triazolo[4,3-a]pyridine-3-(2H)-one to give trazodone base.

Trazodone thus obtained contains alkylating substances used in the process. Since alkylating substances are in general potentially genotoxic; their level in the final drug compound needs to be maintained within very stringent limits.
US 2010/0056539 relates to a process for preparation of trazodone which includes preparing an organic phase comprising trazodone in at least one organic solvent, preparing an aqueous phase comprising at least one basic compound, recovering trazodone. This process is directed to reduce the level of alkylating agents in trazodone.
Thus the reported processes suffers from obtainment of genotoxic impurities like alkylating substances in final compound and these impurities need to be removed by purification.
Hence there is a need to develop a process to prepare trazodone or its salt wherein the product is substantially free of alkylating substances thus minimizing the need of onerous purification.
Accordingly, the present invention provides a process for preparing trazodone or its pharmaceutical^ acceptable salts wherein the desired products are substantially free of alkylating substance and complies with the regulatory requirements for limit of genotoxic impurities like alkylating substances.
OBJECTS OF THE INVENTION
The main objective of the present invention is to provide a process for preparation of Trazodone.

Another object of the invention is to provide Trazodone substantially free of
alkylating substances.
Another object of the invention is to provide novel intermediates of Trazodone and their preparation.
SUMMARY OF THE INVENTION
Accordingly, in one aspect the present invention provides a process to prepare trazodone hydrochloride comprising reaction of 2H-[l,2,4]triazole[4,3-a]pyridine-3-one or its alkali metal salts with sulfonyl derivative of 3-[4-(3-chlorophenyl) piperazine-l-yl]-propan-l-ol to give trazodone and optionally converting it to its pharmaceutically acceptable salt. In another aspect the present invention provides trazodone or its pharmaceutically acceptable salts substantially free of alkylating substances. In yet another aspect the present invention provides compound of formula (IX) and (X).
DETAILED DESCRIPTION
According to the process of present application trazodone or its pharmaceutically acceptable salts are prepared by reacting sulphonyl derivative of formula (X) with triazolo pyridine or its metal salt (XI). The process can be represented as following scheme:


Metal salts of 2H-[l,2,4]triazole[4,3-a]pyridine-3-one (XI) includes salt with alkali metals such as sodium, potassium, cesium or like and can be prepared by reacting triazolo pyridine with alkali metal hydroxide in presence of solvent.
The alkali metal hydroxide used in the process can be selected from sodium hydroxide, potassium hydroxide, cesium hydroxide or like; the solvent used for the reaction can be selected from any suitable solvent such as alkanol, ketone, water or mixture thereof.
The product i.e. compound of formula (XI) can be isolated from the reaction mixture by cooling the reaction mixture below the reaction temperature.
3-[4-(3-chlorophenyl)-piperazine-l-yl]-propan-l-ol of formula (IX) is prepared by reacting l-(3-chlorophenyl)piperazine with 3-chloropropan-l-ol. The reaction can be

carried out in presence of solvent, base and catalytic amount of metal iodide such as sodium iodide. Alternatively, reaction can be carried out in absence of metal iodide.
Alkylating substance of formula (X) is prepared by reacting 3-[4-(3-chlorophenyl)-piperazine-l-yl]-propan-l-ol (IX) with sulfonyl halide. The sulphonyl halide can be selected from methane sulphonyl chloride; 4-toluenesulfonyl chloride etc.The reaction can be carried out in presence of a solvent and base at cooling, ambient temperature or under heating. The product i.e. trazodone base (I) can be isolated by extraction
Alternatively trazodone base can be prepared by reacting 3-[4-(3-chlorophenyl)-piperazin-l-yl]-propan-l-ol with sulfonyl chloride and 2H-[l,2,4]triazole[4,3-a]pyridine-3-one or its alkali metal salt without isolating the intermediate. The reaction can be carried out in presence of solvent and base. The product is isolated by extraction.
Trazodone base thus prepared can be converted to its pharmaceutically acceptable • salt by any known method or by reacting with concentrated hydrochloric acid in presence of methanol. Trazodone hydrochloride can be purified by any suitable organic solvent such as alkanol such as alcohol, isopropyl alcohol, ketone such as acetone, methyl isobutyl ketone, nitrile such as acetonitrile or mixture thereof.
Trazodone and trazodone hydrochloride prepared by above process are substantially free of alkylating substances 3-chloropropan-l-ol, alkylating substance i.e. sulfonyl derivative of formula (X).
3-chloropropan-l-ol (VIII) which is potential genotoxic is used in the process as starting material, and is below the detection level (limit of detection is about 1.25

ppm) by gas chromatography alkylating substance i.e. sulfonyl derivative (X) is easily removed by addition of water to the reaction mixture of trazodone base prior to isolation. Addition of water converts compound of formula (X) into compound of formula (IX) which is not an alkylating substance, this way trazodone can be prepared almost free of alkylating substances.
Trazodone hydrochloride thus prepared by the process of present invention is about 99.95% pure.
The following examples are illustrative of the invention but not limitative of the scope thereof:
EXAMPLES
Example 1: Preparation of sodium salt of 2//-[l,2,4]-triazoIo-[4,3-a]-pyridin-3-one from 2//-[l,2,4]-triazolo-[4,3-a]-pyridine-3-one
32.56 g of sodium hydroxide in water and isopropanol (1000 ml) was added to 100 g of 2H-[l,2,4]-triazole-[4,3-a]-pyridine-3-one at ambient temperature. The mixture was heated at 82-85 °C for 30-40 minutes. The reaction mixture was cooled to 0-5 °C, the product thus precipitated was filtered and dried to give sodium salt of 2H-[l,2,4]-triazolo-[4,3-a]-pyridine-3-one.
Yield: 90-95%

Example 2: Preparation of 3-[4-(3-chIorophenyl)piperazine-l-yl] propan-1-ol
100 g of l-(3-chlorophenyl)-piperazine, 57.68 g of 3-chloro propan-1-ol, 66.75 g of triethylamine and solution of catalytic amount of sodium iodide in toluene (300 ml) were mixed in a reaction flask. The reaction mixture was refluxed till completion of reaction. After completion; reaction mixture was washed with water and title product was crystallized from toluene.
Yield: 85-90%
Example 3: Preparation of trazodone base
100 g of 3-[4-(3-chlorophenyl)-piperazine-l-yl] was dissolved in dimethylformamide (300 ml) followed by addition of 43.6 g of triethylamine at 25-30 °C. The reaction mixture was cooled to 0-5 °C and to it 47.2 g of methane sulfonyl chloride was added. After completion of reaction the reaction mixture was filtered and to the filtrate sodium salt of 2//-[l,2,4]triazole-[4,3-a]-pyridine-3-one (74.0 g) was added, the resultant mixture was heated at 60-70 °C till completion of reaction. The reaction mixture was extracted with ethyl acetate; the gummy mass thus obtained was dissolved in methanol (500ml) and was isolated by addition of water (1500ml).
Yield: 85-90%
Example 4: Preparation of 3-[4(-3-chlorphenyl) piperazine-l-yl]propan-l-ol
100 g of 3-[4-(3-chlorophenyl)-piperazine-l-yl]-propan-l-ol was dissolved in dichloromethane (300 ml) followed by addition of 43.6 g of triethylamine at 25-30

°C. The reaction mixture was cooled to 0-5 °C and to it 47.2 g of methane sulfonyl chloride. After completion of the reaction the reaction mixture was filtered and the filtrate was distilled to get title product.
Example 5: Preparation of trazodone base
100 g of 3-[4(-3-chlorophenyl) piperazine-1-yl] propyl methane sulfonate was dissolved in 300 ml of dimethylformamide. The resultant mixture was cooled to 0-5 °C. To this was added 56.6 g of sodium salt of 2//-[l,2,4]-triazolo-[4,3-#)]-pyridin-3-one from 2j7-[l,254]-triazoIo-[4,3-a]-pyridine-3-one and the reaction mixture was stirred at 60-70 °C till completion of reaction. The reaction mixture was extracted from ethyl acetate and the gummy mass thus obtained was dissolved in methanol (500ml) followed by addition of water (1500ml), the product thus precipitated was filtered and dried to obtain the title compound.
Yield: 85-90%
Example 6: Preparation of trazodone hydrochloride
140 g trazodone base was dissolved in methanol (700ml) followed by addition of 35% of cone. HC1 (47.10 g) at 25-35 °C. The reaction mixture was cooled to 0-5 °C. After 2 hours, the product thus precipitated was filtered and dried to give trazodone hydrochloride.
Example 7: Purification of trazodone hydrochloride
100 g trazodone hydrochloride obtained in example 6 was suspended in acetonitrile (1000ml). The slurry was heated to reflux and after two hours; slurry was cooled up

to 40-45 °C then filtered to obtain pure trazodone hydrochloride.
Method of analysis of compound of formula VIII
Instrumentation: Shimatzu GC 2010 plus with flame ionized detector and auto sampler
Operating Software: Chromeleon
Chromatographic Conditions:

Column DB-624 (30mX0.53mm) 3 um;(Agilent or equivalent)
Column oven temperature program me 40°C-3 .Omin-10°C/min-23 0°C-5min
Carrier gas Nitrogen
Injector Temperature 120 °C
Detector Temperature 260 °C
Flow Control Mode Constant Pressure
Pressure 2.33 psi
Injection Mode Split
Split ratio 1:5
Hydrogen Flow 40 ml/min
Air flow 400 ml/min
Make up flow 30 ml/min
Diluent Ethyl Acetate
Limit of Detection: 1.25 ppm Limit of Quantification: 3.77 ppm

Method of analysis for compound of formula X
Instrumentation:
HPLC system equipped with UV-visible detector, binary/quaternary gradient pump with auto injector and suitable software.
Chromatographic Conditions:

Column
Symmetry shield RP 18(150x4.6)mm,3.5ti, (Make Waters)
Wavelength UV at 248mm
Flow Rate 1 .Oml/min
Injection Volume lOul
Column Oven Temperature 25 °C
Sampler Temperature 5°C
Run Time 60 min
Diluent Acetonitrile
Retention Time of mesyl of formula
(X) About 24 min
Buffer preparation: Dissolve about 1.56g of sodium dihydrogen phosphate dehydrate (NaH2P04.2H20) in 1000ml of water. Addlml of triethylamine and mix well, adjust the pH to 6.00±0.05 with diluted solution of orthophosphoric acid (10% v/v). Filter it through 0.45 (i membrane filter paper and degas.
Mobile Phase A preparation: Prepare a premixed and degassed mixture of buffer and acetonitrile: methanol (80:20) (v/v in the ratio of 30:70 (v/v).

Mobile phase B preparation: Prepare a premixed and degassed mixture of buffer and acetonitrile: methanol (80:20) (v/v) in the ratio of 30:70 (v/v).
Gradient Program me

Time (in minute) Mobile Phase A (% v/v) Mobile Phase B (% v/v)
0.01 100 0
. 10 100 0
45 0 100
50 0 100
52 100 0
60 100 0
Limit of Detection: .03 ppm Limit of qualification: 0.10

Claims:
1. A process to prepare trazodone of formula (I)

or a pharmaceutically acceptable salt; comprising:

with 3-chloro-propan-l-ol of formula (VIII)

to produce 3-[4-(3-chlorophenyl)piperazine-l-yllpropan-l-ol of formula (IX)

a) reacting l-(3-chlorophenyl)piperazine of formula (VII)
(IX) b) reacting 3-[4-(3-chlorophenyl)piperazine-l-yl]-propan-l-ol of formula (IX)
with sulfonyl halide to produce compound of formula (X)

wherein R= methyl, toluyl
c) optionally isolating compound of formula (X)
d) reacting the compound of formula (X) with 2H-[l,2,4]triazole-[4,3-a]-pyridin-3-one or its metal salt of formula (XI)


wherein M+ = alkali metal
to produce trazodone base of formula (I) and optionally converting the trazodone formed into a pharmaceutically acceptable salt.

with 3-chloropropan-l-ol

2. A process as per claim 1, wherein steps a), b) or d) are carried out in presence of solvent and base.
3. A process as claimed in claim 1, wherein metal salt of compound of formula (XI) is selected from alkali metal.
4. A process for preparation of trazodone intermediate, 3-[4-(3-chlorophenyl) piperazine-l-yl]propan-l-ol of formula (IX), comprising: reacting l-(3-chlorophenyl)-piperazine of formula (VII)
to produce 3-[4-(3-cholorophenyl)piperazine-l-yl]propan-l-ol of formula (IX).
5. The process of claim 5, wherein reaction is carried out in presence of a base and solvent.

6. A process for preparation of trazodone intermediate 3-[4-(3-chlorophenyl) piperazine-1-yl] propyl methanesulfonate of formula (X)

Wherein R=methyl, toluyl
comprising reacting 3-[4-(3-chlorophenyl)piperazine-l-ylpropan-l-ol of formula (IX) with sulfonyl halide.
7. A process as per claim 1 or 6; wherein sulfonyl halide is methane sulfonyl chloride.
8. Use of compound of formula (IX) in preparation of trazodone or its pharmaceutically acceptable salt.
9. Use of compound of formula (X) in preparation of trazodone or its pharmaceutically acceptable salt.