FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Process for preparation of Flupentixol"
2. APPLICANT (S)
(a) NAME: Centaur Pharmaceuticals Pvt. Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS: Centaur Pharmaceuticals Pvt. Ltd.
Centaur House, shanti Nagar,VakoIa, Santacruz (e) Mumbai 400055. Tel No. 91-22-66499144 Fax No. 91-22-66499108/112
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Process for preparation of flupentixol
Field of Invention
The present invention relates to the novel process for preparation of 2-[4-[3-[(EZ)-2-
(trifluromethyl)-9H-thioxanthen-9-ylidene]propyl]piperazine-l-yl]ethanol, namely
Flupentixol. The said invention further relates to the effective isolation and purification for the same.
Background of Invention
Flupentixol namely, (2-[4-[3-[(EZ)-2-(trifluromethyI)-9H-thioxanthen-9-ylidene]propyl] piperazine-1-yl] ethanol) formula-I is known as antipsychotic drug. It's used for a long acting injection given two or three weekly to people with schizophrenia who have a poor compliance with medication and suffer frequent relapses of illness.

Also known under the trade name Depixol and Fluanxol.There are various processes used in prior art for the preparation of Flupentixol using different routes.

US 3,282,930 disclosed the reaction of 2-trifluromethyl-9-thiaxanthinone (1) with 3-(4-benzyloxyethyl-l-piperazynil)propyl magnesium chloride (2) in tetrahydrofuron as a solvent at 40 0C for 2 hours, The product (3) is further treated with hydrochloric acid to get (Z./E) 9-[3- (4-hydroxyethyl-3-piperazinyl)propylidene]-2-trifluoromethyl thioxanthene dihydrochioride. The free base is obtained after neutralisation of hydrochloride salt which is treated with Pd/C in acetic acid gives 9-[3-(4-hydroxyethyl-l-piperazinyl)propylidene]-2-trifluoromethyl-thioxanthene. General reaction scheme is as follows: (Scheme-I)

Wherein, Scheme-I
Y -is sulphur
A is ethylene
X is chlorine and B is benzyl

The main draw back of this process is overall yield of the product is very poor more over the hydrogenation process on large scale has potential hazards in terms of industrial
safety.
WO2005037820 disclosed the preparation of Flupentixol in which, allyl magnesium iodide is reacted with 2-trifluromethyl-9-thioxanthon to form trifIuoromethyl-9-allyl-9-thioxanthenol. This is further reacted with acetyl chloride in acetic anhydride to form 2-trifluoromethyl-9-(2-propenyliden)- thioxanthene. This is purified by column chromatography, the pure product is then treated with N-(2-hydroxyethyl) piperazine at 100°C for 7 hours. The excess N-(2-hydroxyethyl) piperazine is distilled off at a temperature of 100-120°C under reduced pressure of 0.2-1 mm/Hg to obtain crude flupentixol residue. The flupentixol crude base is purified to obtained pure base .
In this process allyl chloride and methyl iodide are used which are highly toxic and flammable hence need precaution on large scale. More over, the process also involved column chromatography for purification of intermediate which is cumbersome on large scale.
The present invention provides the novel process for preparation of Flupentixol, which is commercially viable and allows the desired product to be obtained in improved yield without using any chromatographic technique. Also it avoids the usage of any environmentally hazardous chemicals so this instant application having the industrial applicability.

Summary of Invention
The principal object of the present invention is to provide the novel process for producing
Flupentixol namely, (2-[4-[3-[(EZ)-2-(trifluromethyl)-9H-thioxanthen-9-ylidene]propyl] piperazine-1-yl] ethanol) (I), wherein the drawback associated in the prior art processes are avoided. The present invention is schematically represent as below:

Scheme-II
In accordance with preferred embodiment of the present invention for the preparation of
Flupentixol namely, (2-[4-[3-[(EZ)-2-(trifluromethyl)-9H-thioxanthen-9-
ylidene]propyl]piperazine-l-yl]ethanol) (I) comprises the following stages.

In first stage of preparation N,N'-Dimethylamino propyl chloride, emanated from neutralization of N,N'-Dimethylamino propyl chloride hydrochloride is reacted with magnesium in dry tertahydrofuron to form corresponding N,N'-Dimethylamino propyl magnesium chloride referred as "grignard reagent". This grignard reagent is reacted with 2-(Trifluoromethyl)-9H-thioxanthen-9-one to form 9~[3-(dimethylamino)propyl]-2-(trifluromethyl)-9H-thioxanthen-9-ol , which is dehydrated in presence of acid to form N,N-dimethyl-3-[(EZ)-2-(trifluoromethyl)-9H-thioxanthene-9-ylidene]propan-l-amine referred as "thioxanthene base". The thioxanthene base is reacted with 2-(piperazin-l-yl)ethanol to form 2-{4-[3-[(EZ) 2-(trifiuoromethyl)-9H-thioxanthene-9-ylidene] propyl]piperazin-l-yl]ethanol referred as "Flupentixol base".
The flupentixol base further reacted with hydrochloric acid in isopropanol and acetone to form flupentixol dihydrochloride.
Detail description of invention
The description of invention is given in details with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The invention provides an improved process for preparation of 2-{4-[3-[(EZ) 2-
(trifluoromethyl)-9H-thioxanthene-9-ylidene]propyl]piperazin-l-yl]ethanol
dihydrochloride.

The process comprising the steps of:
Step-I (Preparation of 9-[3-(dimethylamino)propyl]-2-(trifiuromethyl)-9H-thioxanthen-
9-ol)

In preparation of 9-[3-(dimethylamino)propyI]-2-(trifluromethyl)-9H-thioxanthen-9-ol) N, N'-dimethylaminoproyl chloride hydrochloride is basified using alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide & extracted in organic solvent such as toluene, xylene and cyclohexane. Further it's grignard reagent is prepared by reacting N,N'-dimethyl aminopropyl chloride base (III) with magnesium metal in dry organic solvent such as tertahydrofuron , methyl tetrahydrofuron, diisopropyl ether and diethyl ether or mixture thereof to form N,N'-dimethyl aminopropyl magnesium chloride (grignard reagent). This grignard reagent is reacted with 2-(Trifluoromethy])-9H-thioxanrhen-9-one (II) in organic solvent media such as tetrahydrofuron, methyl tetrahydrofuron, diethyl ether, isopropyl ether, cyclohexane toluene and n-hexane or mixture thereof. The product 9-[3-(dimethylamino)propyl]-2-(trifluromethyl)-9H-thioxanthen-9-ol (IV) formed is isolated by extracting in organic solvent such as methylene chloride ,chloroform, ethylene dichloride, and ethyl acetate or mixture thereof. This is further purified by aliphatic alcohol such as ethanol, n-propanol, hexanol, heptanol, butanol and iso propyl alcohol or

mixture thereof to get pure 9-[3-(dimethylamino)propyl]-2-(trifluromethyl)-9H-thioxanthen-9-ol (IV).
Step-II (Preparation of N,N-dimethyl-3-[ (EZ)-2-(trifluoromethyl)-9H-thioxanthene-9-ylidene] propan-1-amine)

In second step the 9-[3-(dimethylamino)propyl]-2-(trifluromethyl)-9H-thioxanthen-9-ol (IV) is undergoes dehydration in presence of inorganic acid such as sulphuric acid, phosphoric acid, boric acid, hydrochloric acid, trifluro acetic acid, trifiuro methane sulphonic acid and methane sulphonic acid or mixture thereof at 30 to 80 °C. After completion of reaction, the product is basified and extracted in organic solvent such as toluene, methylene chloride, ethylene dichloride, ethyl acetate, methyl acetate and tertiary butyl methyl ether (TBME) or mixture thereof. The product, N,N-dimethyl-3-[ (EZ)-2-(trifluoromethyl)-9H-thioxanthene-9-ylidene] propan-1-amine (V) is isolated from evaporation of organic layer.

Step-III (Preparation of 2-[4-[3-[(EZ)-2-(trifluoromethyl)-9H-thioxanthene-9-ylidene]propyl]piperazin-l-y!]ethanol (Flupentixol Base)

The third step involves the reaction of N,N-dimethyl-3-[(EZ)-2-(trifluoromethyl)-9H-thioxanthene-9-ylidene]propan-l -amine (V) with 2(piperazin-l-yl)ethanol (VI) in suitable organic solvent such as dimethyl formamide, dimethyl sulphoxide, tertiary butyl methyl ether, ethylene dichloride, xylene, toluene or mixture thereof under nitrogen atmosphere. After completion of reaction, the usual workup, product is extracted in suitable organic solvent such as toluene, cyclohexane, ethyl acetate, methylene chloride, ethylene dichloride, tertiary butyl methyl ether, or mixture thereof. The evaporation of organic solvent gives the 2-[4-[3-[(EZ)-2-(trifluoromethyI)-9H-thioxanthene-9-ylidene]propyl]piperazm-l-yYlemanol (Ilupentixol Base) (V\l). The frupentixol base is purified by preparing salt with organic acid such as formic acid, citric acid, oxalic acid, acetic acid, lactic acid,fumaric acid and maleic acid which is further purified by aliphatic ester solvent such as iso-butyl acetate, iso-amyl acetate, iso- ropyl acetate and ethyl acetate or mixture

thereof and neutralized by potassium carbonate and extracted by organic solvent such as methylene dichloride,ethylene dichloride , cyclohexane or mixture thereof to get flupentixol base.
The flupentixol base purified by ketone solvents such as methyl isobutyl ketone, methyl isopropyl ketone,ethyl isopropyl ketone and acetone or mixture thereof to yield pure flupentixol base.
Step-IV (Preparation of 2-[4-[3-[(EZ) 2-(trifluoromethyl)-9H-thioxanthene-9-ylidene]propyl]piperazin-l-yl]ethanol dihydro chloride )

In stage four, The 2-[4-[3-[(E2)-2-(trifluoromethyl)-9H-thioxanthene-9-ylidene]propyl]piperazin-l-yl]ethanol (Flupentixol Base) is dissolved in acetone and reacted with isopropanolic HO or HC1 gas saturated in diisopropyl ether or in ethyl acetate, at reflux temperature to form 2-[4-[3-[(EZ) 2-(trifluoromethyl)-9H-thioxanthene-

9-ylidene]propyl]piperazin-l-yl]ethanol dihydrochloride, the solid product thus formed is further purified in aliphatic alcohol such as ethanol, n-propanol,iso-prapanol, butanol and methanol or mixture thereof to yield pure flupentixol dihydrochloride. According to present invention wherever, the mixture of organic solvents used are in stiochometry proportion.
While the present invention is described with respect to particular examples and preferred embodiments, it is understood that the present invention is not limited to these examples and embodiments. The present invention as claimed therefore includes variations from the particular examples and preferred embodiments described herein, as will be apparent to one of skill in the art. Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art would appreciate modifications to the invention as describes and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. All references mentioned herein are incorporated in their entirety.

Example-I
Preparation of 9[3-(dimethyIamino)propyl]-2-(trifluoromethyl)-9H-thioxanthen-9-ol:
Charge 0.375 Moles of magnesium metal in dry round bottom flask along with 20 ml tetrahydrofuran under nitrogen atmosphere. 1 ml ethyl bromide was added to reaction mixture at 50 - 55°C, followed by addition of 0.4 mole of N, N'-dimethylamino propyl chloride. After addition maintain the reaction at reflux temperature for 1 - 3 hrs. preferably for 1 hr. and cool the reaction mixture between 0 - 30°C, preferably at 15°C. Dissolve 0.178 moles of 2-(trifluoromethyl)-9H-thioxanthen-9-one in 200 ml of mixture of toluene and tetrahydrofuran (1:1 proportion) and was added to above reaction mixture within 1 hr. period at 0 - 30°C preferably at 15°C. After completion of reaction, reaction mixture was diluted with water and product was extracted in toluene. The toluene layer was charcolized and degassed to give 9-[3-(dimethylamino)propyl]-2-(trifluoromethyl)-9H-thioxanthen-9-ol which was further purified from isopropyl alcohol to give final product in 85% yield.
Preparation of N, N-DimethyI-3[(EZ)-2-(trifluoromethyl)-9H-thioxanthen-9-ylidene]propan-l-amine:
Charge 0.136 moles of 9-[(3-dimethylamino)propyl]-2-(trifluoromethyI)-9H-thioxanthen-9-ol in 2 parts cone, hydrochloric acid in round bottom flask along with 0.66 parts of water. Heat the reaction mixture to 40 - 80°C, preferably at 55°C and maintain for 2 hrs. After completion of the reaction, adjust the pH of the reaction mixture between 8-10

(preferably ~ 8) and extract the base in toluene at elevated temperature, preferably at 65 -70°C. The extracted base in toluene is dried over anhydrous sodium sulfate, charcolized and concentrated under vacuum below 90°C to obtain N, N- DimethyI-3[(EZ)-2-(trifluoromethyl)-9H-thioxanthen-9-ylidene]propan-l-amine in 95% yield.
Preparation of 2-{4-[3-(EZ)-2-(trifluoromethyl)-9H-thioxanthen-9-
yIidene]propyl}piperazin-l-yl]ethanol:
0.129 moles of N, N- Dimethyl-3[(EZ)-2-(trifluoromethyl)-9H-thioxanthen-9-ylidene]propan-l-amine is placed in round bottom flask along with 1.0 mole of 2(piperazin-l-yl)ethanol. Heat the reaction mixture to 100 -15Q°C, preferably at 135°C under nitrogen atmosphere for 12 - 60 hrs, preferably for 20 hrs. After completion of the reaction, the reaction mixture was cooled to 50 - 55DC and was diluted with 10 parts of water. Add 0.16 moles of acetic acid and stir for 10 min. Extract the product in cyclohexane at 45 - 75°C preferably at 50°C. The cyclohexane layer was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum below 80°C to yield 2-{4-[3-(EZ)-2-(trifluoromethyl)-9H-thioxanthen-9-ylidene]propyl}piperazin-l-yl]ethanol in 93 - 97% yield.
Preparation of Fhipentixol Dihydrochloride:
Part A:
Purification of Flupentixol Base:
0.124 moles Flupentixol base was dissolved in 10 parts ethyl acetate at 50 - 55°C and solution was cooled to room temperature. To this solution 0.21 moles of maleic acid was added and heated to reflux temperature for 1 - 10 hrs. preferably for 2.0 hrs. The solid product was isolated by filtration after cooling the reaction mass to room temperature. The isolated mass was purified by treatment with 6 parts of ethyl acetate. The maleate salt was neutralized by treatment with potassium carbonate. The liberated flupentixol

base was extracted in cyclohexane at 45 - 75°C preferably at 50°C. The pure base further isolated by evaporating organic layer under reduced pressure. The flupentixol base was further purified by charcoal treatment in acetone. The evaporation of acetone under reduced pressure gave pure flupentixol base in 90% yield.
Part B:
0.11 Mole of purified base was dissolved in 5 parts of acetone. The pH of the solution was adjusted to 1 - 2 by addition of isopropanolic HC1 or HC1 gas saturated in diisopropyl ether or in ethyl acetate at 30 - 35°C. Heat the reaction mixture to 35 -60°C preferably to 37°C for 1 - 4 hrs. preferably for 1 hr. Cool the reaction mixture to 0 - 5°C and maintained for 6 - 12 hrs. preferably for 8 hrs. The product was isolated by filtration. The isolated product was dried in oven at 35 - 55°C, preferably at 35°C. The crude hydrochloride was isolated in 85% yield.
Part C:
The crude Flupentixol hydrochloride thus obtained from Part B was further purified in methanol and isolated from acetone. The Flupentixol hydrochloride pure was obtained in 90% yield.

Claims:
1. A process for preparing Flupentixol comprising the steps of:
a) condensation of 2-(trifluoromethyl)-9H-thioxanthen-9-one with of N,N' dimethyl aminopropyl magnesium chloride in mixture of dry organic solvents at 0°c to 30°C with example to give 9-3-(dimethylamino)propyl]-2-(trifluoromethyl)-9H-thioxanthen-9-ol and purified by aliphatic alcohol;
b) dehydration of 9-[3-(dimethylamino)propyl]-2-(trifluoromethyl)-9H-thioxanthen-9-ol by using aqueous inorganic acid at elevated temperature for to give N, N- Dimethyl-3 [(EZ)-2-(trifluoromethyl)-9H-thioxanthen-9-ylidene]propan-1-amine;
c) N, N- Dimethyl-3[(EZ)-2-(trifluoromethyl)-9H-thioxanthen-9-ylidene]propan-l-amine condensed with 2-(piperazine-l-yI)ethanol and product i.e 2-{4-[3-(EZ)-2-(trifluoromethyl)-9H-thioxanthen-9-ylidene]propyl}piperazin-l-yl]ethanol (Flupentixol base) isolated from reaction mass by using organic solvent below 80 °C ;
d) purification of Flupentixol base by formation of salt such as malate, citrate, formate with organic acid in aliphatic ester solvent at reflux temperature which is neutralize by potassium carbonate and extracted by cyclohexane to obtain 2-{4-[3-(EZ)-2-(trifluoromethyl)-9H-thioxanthen-9-ylidene]propyl}piperazin-l-yI]ethanol (Flupentixol base) treated with aliphatic ketone solvent to obtain pure flupentixol base ;

e) Flupentixol base obtained in step d is dissolved in isopropanol and treated with hydrochloric gas saturated in di-isopropyl ether Iospropanoi add in ethyl acetate at 35°C-60°Cin acetone and followed by cooling the mixture at 0-5 °C to obtain crude Flupentixol dihydrochloride;
f) crude Flupentixol dihydrochloride crystallized in aliphatic alcohol or aliphatic ketone as a solvents or mixture thereof to obtain pure Flupentixol dihydrochloride;

2) A process for preparing Flupentixol according to claim 1 wherein, solvent media used for condensation is dry organic solvent such as diethyl ether, diisopropyl ether, tetrahydrofuron and toluene or mixture thereof.
3) A process for preparing Flupentixol according to claim 1 wherein, solvent used for condensation is a dry mixture of toluene and tetrahydrofuron in stiochometry proportion.
4) A process for preparing Flupentixol according to claim 1 wherein, aliphatic alcohol solvents used for purification of 9-[3-(dimethylamino)propyl]-2-(trifluoromethyl)-9H-thioxanthen-9-ol are methanol ,ethanol, n-propanol, hexanol, hepatanol, butanol and iso-propyl alcohol or mixture thereof.
5) A process for preparing Flupentixol according to claim 1 wherein, aliphatic alcohol solvent used for purification of 9[3-(dimethylamino) propyl]-2-(trifluoromethyI)-9H-thioxanthen-9-ol is iso-propyl alcohol.

6) A process for preparing Flupentixol according to claim 1 wherein, aqueous inorganic acid such as sulphuric acid, phosphoric acid, boric acid and hydrochloric acid or mixture thereof.
7) A process for preparing Flupentixol according to claim 1 wherein, aqueous inorganic acid is hydrochloric acid.
8) A process for preparing Flupentixol according to claim 1 wherein, organic solvent used for isolation of flupentixol base from reaction mass such as toluene, cyclohexane, ethyl acetate, methylene chloride, ethylene dichloride, tertiary butyl methyl ether, or mixture thereof.
9) A process for preparing Flupentixol base according to claim 1 wherein, base salt formation by using formic acid, citric acid, oxalic acid, acetic acid, lactic acid and maleic acid .
10) A process for preparing Flupentixol base according to claim 9 wherein, base salt
formation by using maleic acid.

11) A process for preparing Flupentixol according to claim 1 wherein, salt formation in aliphatic ester solvent iso-butyl acetate, iso-amyl acetate, iso- propyl acetate and ethyl acetate or mixture thereof.
12) A process for preparing Flupentixol according to claim 11 wherein, salt formation is in ethyl acetate.
13) A process for preparing Flupentixol according to claim 1 wherein, in ketone solvent, is methyl isobutyl ketone, methyl isopropyl ketone,ethyl isopropyl ketone and acetone or mixture thereof.
14) A process for preparing Flupentixol according to claim 13 wherein, ketone solvent is acetone.
15) A process for preparing Flupentixol according to claim 1 wherein, the preparation of flupetixol dihydrochloride is in isopropanol in HC1 or HC1 gas saturated in diisopropyl ether or in ethyl acetate.

4) A process for preparing zopiclone by using alkylation's catalyst according to claim 1 wherein, mole ratio of reactant, 6-(5-chIoropyridyl-2-yl)-5-hydroxy-7-oxo-5, 6-dihydro-pyrrolo [3,4b] pyrazine to alkylation catalyst is preferably 212:1.