FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
L TITLE OF THE INVENTION: "A resolution process for Flupentixol "
2. APPLICANT (S)
3. (a) NAME: Centaur Pharmaceuticals Pvt. Ltd
4. (b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS: Centaur Pharmaceuticals Pvt. Ltd.,Centaur House, shanti Nagar,Vakola, Santacruz (e) Mumbai 400055. ,TeI No. 66499144 Fax No. 66499108/112
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.
Field of Invention
The present invention relates to the process for preparation of Flupentixol in 1:1 to 1: 1.4, E/Z isomeric ratio from Flupentixol isomeric mixture comprising predominately

E-isomer or Z-isomer. The present invention further relates to the process for preparation of Flupentixol dihydrochloride.
Background of the Invention
Flupentixol is neuroletic drug of the thioxanthene group, chemically known as 2-[4-(3-trifluoromethyl-thioxanthen-9-ylidene]-propyl]-pipera2in-l-yl]-ethanol and is represented by structural Formula (I).

Flupentixol is marketed under brand names such as Depixol and Fluanxol, and it is used in treatment of psychotic disorder, particularly for the treatment of
schizophrenia.
Flupentixol exists in two geometric isomeric forms E-isomer and Z- isomer, hereafter referred to as E-flupentixol and Z-flupentixol respectively. According to the pharmacopeial requirement, both these isomer of Flupentixol should be present in approximate ratio of 1:1 in final product.
Following are some of prior art related to isomeric forms of Flupentixol,

US 3,282,930, describes a process for fractionally crystallizing 10[3-[4-(3-benzoyloxypropyl)-1 -piperazinyl propylidene]-2-trifluoromethyl thiaxanthene dihydro chloride to obtain the separate Z and E isomer-
US 3,681,346, described the separation of the Z and E isomers of flupentixol by the fractional crystallization of flupentixol base from ethyl ether as a solvent.
GB925538, described that the separation of E/Z isomer of flupentixol can be carried out by the fractional crystallization of the dihydrochloride.
EP1673365, described a process for separation of isomers of flupentixol, particularly to process for the preparation of 2-flupentixol and its decanoate ester and novel synthetic intermediates thereof.
CN200910184530, described the method for separating flupentixol hydrochloride isomers by dissolving flupentixol in organic solvent and adding hydrogen chloride in different molar ratio and precipitation out E-flupentixol hydrochloride.
None of the prior art directly or indirectly provides the process for preparation of Flupentixol E/Z isomer ratio about 1:1 to 1:1.4 from Flupentixol isomeric mixture comprising predominately E-isomer or Z-isomer. The inventors of present invention have skillfully developed a simple and efficient process for obtaining Flupentixol E/Z ratio about 1:1 to 1: 1.4.

Summary of the Invention
According to an aspect of present invention, there is provided a process for obtaining Flupentixol E/Z isomer ratio about 1:1 to 1: 1.4 comprising; treating Flupentixol isomeric mixture containing predominately E-isomer with base in organic solvent at a temperature ranging from 0 to 120°C.
Similarly an aspect of present invention, there is provided a process for obtaining Flupentixol E/Z isomer ratio about 1:1 to 1: 1.4 comprising; treating Flupentixol isomeric mixture containing predominately Z-isomer, with base in organic solvent at a temperature ranging from 0 to 120°C.
More particularly, there is provided a process for isomerisation of mixture of E/Z isomers of flupentixol comprising 100% of E-isomer and 0 % of Z-isomer or 100 % of Z-isomer and 0 % of E-isomer obtain Flupentixol E/Z isomer ratio of 1:1 to 1:1.4, by treatment with base in organic solvent at a temperature ranging from 0 to 120°C.
Another aspect of the present invention is to provide the process for preparation of Flupentixol dihydrochloride.
Detailed Description of the Invention
According to an aspect of present invention, there is provided a process for obtaining Flupentixol E/Z isomer ratio about 1:1 to 1:1.4 comprising; treating Flupentixol isomeric mixture containing predominately E-isomer or Z-isomer, with base in organic solvent at temperature ranging from 0 to 120°C.
More particularly, there is provided a process wherein isomeric mixture of Flupentixol comprising more :han 100% of E-isomer and 0 % of Z-isomer or 100 % of Z-isomer and 0% of E-isomer is subjected to treatment with base in organic

solvent at a temperature ranging from 0 to 120°C to obtain Flupentixol E/Z isomer ratio about 1:1 to 1:1.4.
The isomeric mixture of Flupentixol used as starting material comprises more than 100% of E-isomer and 0% of Z-isomer or 100 % of Z-isomer and 0 % of E-isomer.
According to an another aspect of present invention, there is provided a process for obtaining Flupentixol dihydrochloride comprising;
a) treating Flupentixol isomeric mixture containing predominately E-isomer, with a strong base in an polar organic solvent at a temperature ranging from 0°C to 120°C;
b) distilled out the solvent from step a) under reduced pressure and added organic solvent;
c) extracting the organic layer obtained in step b) by water and concentrate the organic layer under reduced pressure to obtained residue of flupentixol;
d) adding acetone in residue obtained in step c), followed by Isopropyl alcohol and hydrochloric acid in equal proportion to get flupentixol dihydrochloride;
e) Treating the obtained product in step d) by convention way to obtain the free base of flupentixol.
The base used is selected from alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, alkali metal carbonate such as sodium carbonate or potassium carbonate, alkali metal salts of CI -C7 alkoxide such as sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or lithium methoxides, or nucleophlic catalyst like 4-dimethyl aminopyridine (DK4AP).

The molar ratio of base used with respect to E/Z isomeric mixture of Flupentixol used as starting material is in range of 1 to 2.5.
The organic solvent used is selected from non-polar or polar solvent. The non-polar solvent used is selected from diethyl ether, toluene, xylene and monochlorobenzene or mixtures thereof.
The polar solvent used is selected from polar protic solvent like alcoholic solvent such as IPA, butanol, n-propanol, methanol, benzyl alcohol, tert. butanol, amyl alcohol, ethylene glycol or polar aprotic solvent such as methylene chloride, ethylene chloride, chloroform or keton'c solvent such as acetone, ethyl ketone, methyl ethyl ketone, methyl tert-butyl ether and mixtures thereof.
The amount of solvent used with respect to isomeric mixture of Flupentixol used as starting material is in range of 5 to 15 volumes.
According to an embodiment of present invention, the process provides Flupentixol E/Z isomer ratio about 1:1 to 1:2 but more particularly 1: 1.4.
According to present invention, for conversion of Flupentixol in 1:1 to 1: 1.4, E/Z isomeric ratio from Flupentixol isomeric mixture comprising predominately E-isomer the solvent system and proper base selection plays a vital role wherein the Inventors of the present invention skillfully designed the combination of solvent system and selective base in order to get the fruitful outcome.
The following examples illustrate the invention but are not to be constructed as limiting the same. All E/Z isomeric ratio were obtained by high performance liquid chromatography (HPLC) analysis.

Example: 1
Sodium hydroxide (0.95 gm, 23.75 moles) was added with stirring at room temperature under nitrogen to a suspension of Flupentixol (5 gm, 11.5 moles, 94.6% E-isomer, E/Z ratio 1:17.5) in IP A (50 ml) and mixture stirred for 3 hours at reflux temperature. Analysis of reaction showed 54.8% of E isomer and 45.2% of Z isomer. The mixture was concentrated to a residue by the distillation of the solvent under reduced pressure and 100 ml of Toluene was added. Cool to 25-30°C and add 50 ml of water. The two phases was separated and aqueous phase extracted with 50 ml Toluene. The organic phase was combined and washed with 100 ml of water. The organic phase is concentrated to a residue by distillation of the solvent under reduced pressure. To residue was added acetone (50 ml) followed by drop wise addition of isopropyl alcohohhydrochloric acid solution over a period of 15 min. The mixture was then refluxed for 1 hr, cooled to.0-5°C and maintained for 2 hrs. the solid was filtered and washed with chilled acetone. The filtrate was dried at 50°C and 4.5 gm of flupentixol dihydrochloride was obtained (54.4% E-isomer and 45.6% Z-isomer. E/Z ratio 1:1.19).
Treating the flupentixol dihydrochloride by convention way to obtain the free base of flupentixol with desired ratio.
Example: 2
Sodium-t-butoxide (1.42 gm. 14.7 moles) was added with stirring at room temperature under nitrogen to a suspension of flupentixol (5 gm, 11.5 moles, 84.2% E-isomer, E/Z ratio 1:5.3) in xylene (50 ml) and mixture stirred for 3 hours at reflux temperature. Analysis of reaction showed 54.8% of E isomer and 45.2% of Z isomer. Reaction mixture was cool to 25-30°C and added 50 ml of water. The two phases was separated and aqueous phase extracted with 50 ml Toluene. The organic phase was

combined and washed with 100 ml of water. The organic phase was concentrated to a residue by distillation of the solvent under reduced pressure. To residue was added acetone (50 ml) followed by drop wise addition of isopropyl alcohol: hydrochloric acid solution over a period of 15 min. The mixture was then refluxed for 1 hr, cooled to 0-5°C and maintained for 2 hrs. The solid was filtered and washed with chilled acetone. The filtrate was dried at 50°C and 4.5 gm of ilupentixoi dihydrochloride was obtained (54.8% E-isomer and 45.2% Z-isomer, E/Z ratio 1:1.21). Treating the flupentixol dihydrochloride by convention way to obtain the free base of flupentixol with desired ratio.
Example: 3
Potassium hydroxide (2.2 gm, 39.2 moles) was added with stirring at room temperature to a suspension of E-flupentixol dihydrochloride (10 gm, 19.7 moles, 98.5% E-isomer, E/Z ratio 1:65.7) in 1PA (100 ml). The reaction mixture stirred for 3-4 hours at reflux temperature. Analysis of reaction mixture was showed 54.6% of E isomer and 45.5% of Z isomer. The mixture was concentrated to a residue by the distillation of the solvent under reduced pressure and 100 ml of dichloromethane and 50 ml of water was added. The two phases was separated and aqueous phase extracted with 50ml dichloromethane. The organic phases were combined and wash with 100 ml water. The organic phase was concentrated to a residue by distillation of the solvent under reduced pressure and 100 ml of acetone was added. Isopropyl alcohohhydrochloric acid solution was added drop wise over a period of 15 min. The mixture was then refluxed for 1 hr, cooled to 0-5°C and maintained for 2 hrs. The solid was filtered and washed with chilled acetone. The filtrate was dried at 50°C and 7 gm of flupentixol dihydrochloride was obtained (54.5% E-isomer and 45.5% Z-isomer, E/Z ratio 1:1.19).

Treating the flupentixol dihydrochloride by convention way to obtain the free base of flupentixol with desired ratio.
Example: 4
Potassium hydroxide (4 gm, 71.2 moles) was added with stirring at room temperature to a suspension of Z-flupentixol dihydrochloride (10 gm, 19.7 moles, 68.56% Z-isomer, E/Z ratio 1:0.45) in IPA (100 ml). The reaction mixture stirred for 3-4 hours at reflux temperature. Analysis of reaction mixture was showed 54.52% of E isomer and 45.47% of Z isomer. The mixture was concentrated to a residue by the distillation of the solvent under reduced pressure and 100 ml of dichloromethane and 50 ml of water was added. The two phases was separated and aqueous phase extracted with 50 ml dichloromethane. The organic phases were combined and wash with 100 ml water. The organic phase was concentrated to a residue by distillation of the solvent under reduced pressure and 100 ml of acetone was added, lsopropyl alcohol:hydrochloric acid solution was added drop wise over a period of 15 min. The mixture was then refluxed for 1 hr, cooled to 0-5°C and maintained for 2 hrs. The solid was filtered and washed with chilled acetone. The filtrate was dried at 50°C and 6 gm of flupentixol dihydrochloride was obtained (54.52% E-isomer and 45.48% Z-isomer, E/Z ratio 1:1.19).
Treating the flupentixol dihydrochloride by convention way to obtain the free base of flupentixol with desired ratio.

We claim
1. A process for obtaining Flupentixol in approximate E/Z ratio of about 1:1 to
1:4 comprising;
a) treating Flupentixol isomeric mixture containing predominately E-isomer or Z-isomer with a strong base in an organic solvent at a temperature ranging from 0°C to 120°C;
b) distilled out the solvent from step a) under reduced pressure and adding organic solvent;
c) extracting the organic layer obtained in step b) by water and concentrate the organic layer under reduced pressure to obtained residue of flupentixol;
d) adding acetone in step c), followed by Isopropyl alcohol and hydrochloric acid to get flupentixol dihydrochloride:
e) treating the obtained product in step d) by conventional or traditional way to obtain the free base of flupentixol.
2. A process wherein isomeric mixture of Flupentixol comprising more than
100% of E-isomer and 0 % of Z-isomer or 100 % of Z-isomer and 0 %'of E-
isomer is subjected to treatment with a base in organic solvent at a
temperature ranging from 0 to 120°C to obtain Flupentixol E/Z isomer ratio
about 1:1 to 1:1.4.

3. The process as claimed in claim 1 or 2, wherein base used is selected from alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, alkali metal carbonate such as sodium carbonate or potassium carbonate, alkali metal salts of C1 -C7 alkoxide such as sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or lithium methoxides, or nucleophlic catalyst like 4-dimethyl aminopyridine (DMAP).
4. The molar ratio of base used with respect to isomeric mixture of Flupentixol used as starting material is in range of 1 to 2.5
5. The process as claimed in claim 1 or 2, wherein the organic solvent used is selected from polar or non-polar solvent.
6. The process as claimed in claim 5, wherein the polar solvent used is selected from polar protic solvent like alcoholic solvent such as 1PA, butanol, n-propanol, methanol, benzyl alcohol, tert. butanol, amyl alcohol, ethylene glycol or polar aprotic solvent such as methylene chloride, ethylene chloride. chloroform or ketonic solvent such as acetone, ethyl ketone, methyl ethyl ketone, methyl tert butyl ether and mixtures thereof.

7. The process as claimed in claim 4. wherein the non-polar solvent used is selected from toluene and xylene and monochlorobenzene or mixtures thereof but preferably toluene.
8. The amount of solvent used with respect to isomeric mixture of Flupentixol used as starting material is in range of 5 to 15 volumes.