FORM 2
THE PATENTS ACT, 1970
(Act 39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See Section 10 & rule 13)
"AN IMPROVED PROCESS FOR THE PREPARATION OF l-(2,3-DICHLOROPHENYL)PIPERAZINE AND ITS SALT THEREOF"
ZCL CHEMICALS LIMITED
'A'-806/807,
215 ATRIUM CHAKALA,
ANDHERI (EAST), MUMBAI-400 059,
MAHARASHTRA, INDIA.
(An Indian Organization)
The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF 1(2,3-DICHLOROPHENYL)PIPERAZINE AND ITS SALT THEREOF FIELD OF THE INVENTION
The present invention relates to a process for the preparation of l-(2.3-dichloro-phenyl)piperazine and its salt thereof.

BACKGROUND OF THE INVENTION
US 2,922,788 and GB 850,663 discloses the processes for producing related phenylpiperazine compounds have been described, In which mixture of 2.3-dichloroaniline and diethanolamine treated with concentrated hydrochloric acid and heated up to 220-225°C followed by adding alkali and the reaction mixture is extracted with the ether. The extract is washed with water and 5N sodium hydroxide solution. Then ether is removed under vacuum distillation to get 1 -(2.3-dichlorophenyl)piperazine free base. The free base is then converted to monohydrochloride and treated with isopropanol to remove excess hydrogen chloride. Further the obtained hydrochloride salt of l-(2,3-dichlorophenyl)piperazine is crystallized in isopropanol.
./. Am. Chem. Soc. (1954), 76. 1853-1855 discloses the preparation of related compound l-(4-chlorophenyl)piperazine required continuous water distillation and vacuum distillation or fractional distillation to remove low boiling materials get pure product which is difficult to manage on a large scale.
In Bioorganic and Medicinal Chemistry Letters (1998), 8, 2715-2718, discloses the synthesis of l-(2,3-dichlorophenyl)piperazine from 2,3-dichloroaniline

and diethanoiamine in presence of P2O5, triethylamine and HC1. This process has the following disadvantages like heating upto 200°C. which is difficult to achieve at large scale, extraction in chloroform, purification of the final product by column chromatography and yield reported is very low (21 %).
Another process is described in J. Med. Chem. (1965), 8, 104-107 for the preparation of l-(2,4-dichlorophenyl)piperazine, but it requires extraction in benzene as well as crystallization in benzene making it unsuitable for large-scale application.
The general process for the preparation of piperazines reported in ./. Med. Chem. (1989), 32, 1052-1 056 involving 1-butanol as a solvent gives lower yield of product (21%).
Chem. Pharm. Bull 47(12) 1679-1684 (1999), discloses the preparation of related compound l-(3-chloro-4-hydroxyphenyl)piperazine.HCI by reacting mixture of 2-chloro-4-aminophenol and bis(2-chloroethyl)amine hydrochloride in n-BuOH is refluxed for 20 hours. Anhydrous sodium carbonate is added to the mixture. After being stirred for 8 hours, the reaction mixture was cooled and the precipitate obtained is filtered. The precipitate was suspended with water and extracted with chloroform. The organic phase was washed with water, dried, and evaporated in vacuo. Diethyl ether and IN HCl/EtOH are added to the residue, and the precipitate obtained is filtered to give 28% yield, which is not commercially viable at large scale.
./. Chem. Pharm. Res., 2010, 2(5), 506-517 & Int. ./. Pharm. Sci. Rev. Res., 2010. 5(2) 124-131 discloses the process for 1 -(2,3-dichlorophenyl)piperazine hydrochloride. The mixture of bis-(2-chloroethylamine) hydrochloride, 2,3-dichloroaniline, p-toluenesulphonic acid (PTSA) in xylene is heated to reflux at 140-145°C for 27 hours. On completion, the reaction mass is cooled to 30°C and further chilled to 0-5°C when product crystallizes as off-white crystals. The product is isolated by filtration and washed with chilled xylene followed by acetone for removal

of aniline traces before drying in oven to give 82.0% yield. The process is silent about the purity of the product. As per observation of the scientist of the present invention, that condensation for 27 hours with given condition is not sufficient for the completion of the reaction. The starting material will remain unreacted in large quantity. Hence plenty of acetone washes are required to remove the aniline traces.
IN 249176 discloses the process for the preparation of l-(2,3-dichlorophenyl)piperazine hydrochloride by reacting 2,3-dichloroaniline with bis-(2-chloroethyl) amine hydrochloride in xylene at reflux temperature for extended hours. The mixture is cooled and filtered. The obtained residue is dissolved in water and filtered. The filtrate is basified and extracted with toluene, then separated organic layer is acidified with isopropanolic HC1 to give crude material. Then the obtained crude material purified with alcohol to give 52% l-(2,3-dich!orophenyl)piperazine hydrochloride having purity about 99% and assay reported is only 94%.
As per the observation of scientist of the present invention, the process disclosed in IN 249176 need very much long reaction hours [i.e more than 75-80 hours] for the condensation of 2,3-dichloroaniline with bis-(2-chloroethyl)amine hydrochloride with lower yield. Further yield is decreased by the purification in alcohol. The reported yield after purification is just 52% as well as assay is just 94%. Hence the process is not productive from the industrial point of view.
Thus, present invention fulfills the need of the art to provide an improved and industrially applicable process for preparation of l-(2,3-dichlorophenyl)piperazine hydrochloride by minimize the long reaction time, gives purer product with high yield which makes the process economically viable.

OBJECTIVE OF THE INVENTION
The principal objective of the present invention is to provide a process for preparation of l-(2.3-dichlorophenyl)piperazine hydrochloride to overcome or ameliorate one of the disadvantages of the prior art processes.
Another leading objective of the present invention is to provide 1 -(2,3-dichlorophenyl)piperazine hydrochloride in high yield as well as good quality.
Yet another primary object of the present invention is to provide process for the preparation of l-(2,3-dichlorophenyl)piperazine hydrochloride wherein reaction time is decreased than reported in the prior art processes.
Yet another principle objective of the present invention is to provide purification process to obtain l-(2,3-dichlorophenyl)piperazine hydrochloride of very high purity and assay.
Another prime objective of the invention is to provide an efficient, improved and industrially advantageous process for preparation of l-(2,3-dichlorophenyi)piperazine hydrochloride which is conveniently applicable to industrial scale.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of 1 -(2,3-dichlorophenyl)piperazine hydrochloride,


comprises the steps of:
a), reacting 2,3-dichloroaniline with bis-(2-chloroethyl)amine hydrochloride
in suitable solvent in the presence of catalyst; b). treating with aqueous hydrochloric acid; c). isolating l-(2.3-dichlorophenyl)piperazine hydrochloride; and d). purifying l-(2,3-dichlorophenyl)piperazine hydrochloride in mixture of
alcohols and water.
Or d). purifying l-(2.3-dichlorophenyl)piperazine hydrochloride in mixture of
ketone solvent and water.
Or d) purifying l-(2,3-dichlorophenyl)piperazine hydrochloride in mixture of
isopropanol and water.
Accordingly, the present invention provides a process for the purification of 1 -(2,3-dichlorophenyl)piperazine hydrochloride in mixture of methanol, isopropanol and water thereof.
Accordingly, the present invention provides a process for the purification of 1 -(2.3-dichlorophenyl)piperazine hydrochloride in mixture of isopropanol and water thereof.
Accordingly, the present invention provides a process for the purification of 1 -(2,3-dichlorophenyI)piperazine hydrochloride in mixture of acetone and water thereof.
Accordingly,, the present invention provides an improved process for the preparation of l-(2,3-dichlorophenyl)piperazine hydrochloride as depicted in detailed description.

DETAILED DESCRIPTION OF THE INVENTION
All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "generally" and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
According to the embodiment of the invention provides an industrially feasible and economically viable process for preparation of t-(2,3-dichlorophenyl)piperazine hydrochloride from 2,3-dichloroaniline.
Stage 1:
2,3-dichloroaniline is reacted with bis-(2-chloroethyl)amine hydrochloride to give l-(2,3-dichlorophenyl)piperazine hydrochloride. Generally the reaction involves treatment of 2,3-dichloroaniline with bis-(2-chloroethyl)amine hydrochloride in suitable solvent in the presence of catalyst. Wherein the suitable solvent can be selected from the group of alcohol, aromatic hydrocarbon and/or halogenated solvent. Alcohol include n-butanol, isobutanol, sec-butanol, 3-methylbutan-2-ol, panten-1-ol, 3-methyl-1-butanol, 2-methyl-l-butanol, 2,2-dimethyipropan-1 -ol, 3-pentanol, 2-pentanol, 3-methylbutan-2-ol, 2-methyl-2-butanol and the like or mixtures thereof, aromatic hydrocarbon include toluene, xylene or mixtures thereof, halogenated solvent include chlorobenzene, dichlorobenzene. methylene chloride, chloroform and the like or mixtures thereof. Catalyst can be selected from hydrofluoric acid, phosphoric acid, p-toluenesulphonic acid, polystyrene sulphonate, heteropoly acids, zeolites and graphene oxide and the like. The reaction mixture is heated to 130-150°C preferably 140-150°C, more preferably 140-145°C for 30-70 hours, preferably 40-60 hours, more preferably 50-55 hours. The completion of the reaction can be

monitored by high performance liquid chromatography or thin layer chromatography. After confirmation of reaction completion, the reaction mixture is cooled to 10-60°C. more preferably 35-40°C. The work up procedure can be followed by adding water in the slurry mass and stirred. The layers of biphasic reaction mixture are separated and aqueous layer is extracted with aromatic hydrocarbon solvent as described above, preferably toluene. The biphasic solution is then treated with dilute alkali solution and stirred for a while. Wherein alkali can be selected from the group consisting of sodium hydroxide, potassium hydroxide, lye, calcium hydroxide, magnesium hydroxide and the like. The layers are separated and organic layer is given optional charcoal treatment for the decolorization of product. Into the organic layer suitable solvent is added followed by addition of aqueous hydrochloric acid and stirred for the appropriate time at 25-30°C. Wherein suitable solvent can be selected from acetone, butanone, ethyl isopropyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, mesityl oxide or mixtures thereof. The reaction mixture is then cooled to 0-5°C, filtered and dried to give l-(2,3-dichlorophenyl)piperazine hydrochloride in good yield as well as purity. The assay of l-(2,3-dichlorophenyl)piperazine hydrochloride is not less than 92% and having purity greater than 97.0%.
The major advantage of the stage is to avoid extended reaction hours, essentially reduce unreacted starting material as well as getting more yield and purity in comparison with available prior art.
Stage 2A:
The obtained l-(2,3-dichlorophenyl)piperazine hydrochloride from stage 1 is purified in solvent mixture of two or more alcohol and water. Wherein alcohol include methanol, ethanol. propanol, isopropanol, butanol, sec-butanol, isobutanol and the like or mixtures thereof, preferably combination of two or more alcohols, more preferably methanol and isopropanol in combination with water, preferably in ratio of methanol:isopropanol:water::l-4:l-8:l-4. more preferably in ratio of 1-3:4-

8:1-2. The reaction mixture is heated to 40-100°C, preferably 50-60°C until the reaction mixture gets clear. Charcoal treatment is optionally given for the decolorization of the product. The reaction mixture is cooled to 25-30°C and further cooled to 0-5°C. The precipitated solid is filtered and dried to give purer l-(2,3-dichlorophenyl)piperazine hydrochloride having HPLC purity more than 99.0%, more particularly >99.5%, even more particularly >99.7% and having assay by HPLC is greater than 99.0%.
Stage 2B:
The obtained l-(2,3-dichlorophenyl)piperazine hydrochloride from stage 1 is purified in ketone solvent and water. Wherein ketone solvent include acetone, butanone, ethyl isopropyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, mesityl oxide or mixtures thereof. The reaction mixture is heated to 40-60°C. preferably 50-55°C until the reaction mixture gets clear. Charcoal treatment is optionally given for the decolorization of the product. The reaction mixture is cooled to 25-30°C and further cooled to 0-5°C. The precipitated solid is filtered and dried to give purer l-(2,3-dichloropheny])piperazine hydrochloride having HPLC purity more than 99.0%o, more particularly >99.5%, even more particularly >99.7% and having assay by HPLC is greater than 99.0%.
Stage 2C:
The obtained l-(2.3-dichloropheny])piperazine hydrochloride from stage 1 is purified in alcohols and water. Wherein alcohol solvent include methanol, ethanol, isopropanol, isobutanol and the like or mixtures thereof in combination with water. The reaction mixture is heated to 40-65°C, preferably 55-60°C and stirred for 30-40 minutes. Then reaction mixture is gradually cooled to 25-30°C under stirring and further cooled to 0-5°C. The precipitated solid is filtered and dried to give purer 1-(2,3-dichlorophenyl)piperazine hydrochloride having HPLC purity more than 99.0%,

more particularly >99.5%, even more particularly >99.7% and having assay by HPLC is greater than 99.0%.
The obtained l-(2,3-dichlorophenyl)piperazine hydrochloride can be converted into aripiprazole by the known and conventional techniques.
The invention is further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES:
Stage-1: Preparation of l-(2,3-dichlorophenyI)piperazine hydrochloride
To the mixture of bis-(2-chloroethyl) amine hydrochloride (132.2 gm, 0.741 mol) and mixed xylene (300 ml), p-toluenesulphonic acid (5.0 gm, 0.026 mol) was added at temperature 25-30°C. Then the reaction mixture was added 2,3-dichloroaniline (100.0 gm, 0.617 mol) and stirred for 10-15 minutes. Then the reaction mixture was heated at 140-145°C under stirring for 50-55 hours followed by cooling at 35-40°C. The water (500.0 ml) was added in the slurry mass and stirred for 2 hours. The aqueous layer was separated from biphasic reaction mixture. Toluene (400.0 ml) was charged in the obtained aqueous layer followed by drop wise addition of 50% sodium hydroxide (200.0 gm) solution. The reaction mixture was stirred for 1-2 hours at 25-30°C. Separated the aqueous layer. Further toluene (100.0 ml) was added into the . aqueous layer and stirred for 30 minutes. Then again aqueous layer was separated. Combined the toluene layers and stirred for 10-20 minutes. Water (100.0 ml) was added into the toluene layer and separated the layers and charcoal treatment was given for the decolorization. Then acetone (50.0 ml) was added into the toluene layer followed by drop wise addition of 30% aqueous hydrochloric acid (80.0 gm) and stirred for 30 minutes. The reaction mixture was cooled to 0-5°C, filtered and dried to give l-(2.3-dichlorophenyl)piperazine hydrochloride (130-140 gm). Molar yield: 78-85%

HPLC Purity: >97.0%
Stage-2A: Purification of l-(2,3-dichlorophenyl)piperazine hydrochloride
l-(2,3-dichlorophenyl)piperazine hydrochloride (100.0 gm) was added into methanol (650.0 ml) and the reaction mixture was heated at 55-60°C under stirring until the reaction mixture gets clear. Charcoal treatment was given for the decoiorization followed by distillation of methanol at 60°C. Water (50.0 ml), methanol (80.0 ml) and isopropanol (400.0 ml) were added into the reaction mixture under stirring at 40-50°C. The reaction mixture was heated to 50-55oC for about 30 minutes under stirring. Then cooled to 25-30°C and further at 0-5°C with stirring for 1 hour. The precipitated solid was washed, filtered and dried to give pure 1 -(2,3-dichlorophenyl)piperazine hydrochloride (70-75 gm). Yield: 70-75w/w HPLC Purity: >99.8%, Assay via HPLC: >98%
Stage-2B: Purification of l-(2,3-dichlorophenyI)piperazine hydrochloride
l-(2,3-dichlorophenyl)piperazine hydrochloride (50.0 gm) was added acetone (80.0 ml) and water (20.0 ml). The reaction mixture was heated up to 50-55°C under stirring until the reaction mixture gets clear. Charcoal treatment was given for the decoiorization. The reaction mixture was gradually cooled 25-30°C under stirring and further cooled to 0-5°C with stirring for 1-2 hours. The reaction mixture was washed, filtered and dried to give l-(2,3-dichlorophenyl)piperazine hydrochloride (35-37gm). Yield: 70-74w/w HPLC Purity: >99.8%, Assay via HPLC: >98%
Stage-2C: Purification of l-(2,3-dichlorophenyl)piperazine hydrochloride
l-(2,3-dichloropheny!)piperazine hydrochloride (50.0 gm) was added isopropanol (200.0 ml) and water (20.0 ml). The reaction mixture was heated up to 55-60°C under

stirring for about 30-40minutes. Charcoal treatment was optionally given for the decolorization. The reaction mixture was gradually cooled 25-30°C under stirring and further cooled to 0-5°C with stirring for 1-2 hours. The reaction mixture was washed, filtered and dried to give l-(2.3-dichlorophenyl)piperazine hydrochloride (35-37gm). Molar yield: 70-74w/w HPLC Purity: >99.8%, Assay via HPLC: >98%

WE CLAIM:
1. A process for the preparation of l-(2,3-dichlorophenyl)piperazine hydrochloride.

comprising the steps of: a), reacting 2,3-dichloroaniline with bis-(2-chloroethyl)amine hydrochloride
in suitable solvent in the presence of catalyst: b). treating with aqueous hydrochloric acid; c). isolating l-(2,3-dichlorophenyl)piperazine hydrochloride; and d). purifying l-(2,3-dichlorophenyl)piperazine hydrochloride in mixture of
alcohols and water.
Or d) purifying l-(2,3-dichlorophenyl)piperazine hydrochloride in mixture of
ketone and water.
Or d) purifying l-(2,3-dichlorophenyl)piperazine hydrochloride in mixture of
isopropano! and water.
2. The process according to claim 1. wherein suitable solvent is selected from the group of alcohol include n-butanol. isobutanol. sec-butanol, 3-methylbutan-2-ol. panten-l-ol, 3-methyl-l-butanoi. 2-methyl-l-butanol. 2,2-dimethylpropan-l-ol. 3-pentanol. 2-pentanol. 3-methylbutan-2-ol, 2-methyl-2-butanol or mixtures thereof, aromatic hydrocarbon include toluene, xylene or

mixtures thereof, halogenated solvent include chlorobenzene, dichiorobenzene, methylene chloride, chloroform or mixtures thereof.
3. The process according to claim I, wherein catalyst is selected from hydrofluoric acid, phosphoric acid, p-toluenesulphonic acid, polystyrene sulphonate, heteropoly acids, zeolites and graphene oxide and the like.
4. The process according to claim 1, wherein alcohols are selected from methanol, ethanol, propanol. isopropanol, butanol, sec-butanol. isobutanol and mixtures thereof.
5. The process according to claim 4, wherein alcohols are more preferably mixture of methanol and isopropanol in combination with water, preferably in ratio of methanol:isopropanol:water::l-4:l-8:l-4, more preferably in ratio of
1-3:4-8:1-2.
6. The process according to claim 1, wherein ketone solvent is selected from acetone, butanone, ethyl isopropyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, mesityl oxide or mixtures thereof.
7. A process for the purification of l-(2,3-dichlorophenyl)piperazine hydrochloride comprising;
purifying l-(2,3-dichlorophenyl)piperazine hydrochloride in mixture of
alcohols and water.
Or
purifying l-(2,3-dichlorophenyl)piperazine hydrochloride in mixture of
ketone solvent and water.
Or

purifying l-(2,3-dichlorophenyl)piperazine hydrochloride in mixture of isopropanoi and water.
8. The process according to claim 7, wherein alcohols are selected from methanol, ethanol, propanol, isopropanoi, butanol, sec-butanol, isobutanol and the like or mixtures thereof
9. The process according to claim 8, wherein alcohols are more preferably mixture of methanol and isopropanoi in combination with water, preferably in ratio of methanol:isopropanol:water::l-4:l-8:l-4, more preferably in ratio of 1-3:4-8:1-2.
10. The process according to claim 7, wherein ketone solvent is selected from acetone, butanone, ethyl isopropyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, mesityl oxide or mixtures thereof.