FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"A PROCESS FOR THE PREPARATION OF FLUPENTIXOL DECANOATE"
Centaur Pharmaceutical Private Limited, an Indian Company, having its Registered Office at Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East), Mumbai-Maharashtra, 400055, India
1. The following specification describes the invention.
Technical field of the invention:
The present invention relates to a resolution of Flupentixol; the compound represented by structural formula (II) containing a mixture of E and Z isomer using mandelic acid to obtain mandelate salt of Z- Flupentixol. The mandelate salt of Z-Flupentixol is used for the synthesis of Flupentixol decanoate; the compound represented by structural formula (I) in its pure (Z) form.


Background of the invention:
Z-Flupentixol Decanoate represented by structural formula (I) is chemically known as 2-[4-[(3Z)-3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-l-yl]ethyI decanoate and was first disclosed in U.S. patent number 3,681,346. It is Melatonin Receptor Agonists indicated for the treatment of schizophrenia. It is also used in low doses as an antidepressant. It is commercially sold under the brand name FLUANXOL®. Flupentixol; the compound represented by structural formula (II) was first disclosed in U.S. patent number 3,282,930.

U.S. patent number 3,282,930 discloses the Flupentixol; the compound represented by structural formula (II) generically and its acid addition salt as a mandelic acid salt in general description. However, the resolution of cis and trans isomer is disclosed by preparation of dihydrochloride salt and further fractional crystallization from ethanol-ether. US'930 describe a process for fractionally crystallizing dihydrochloride salt of Flupentixol; the compound represented by structural formula (II). This is industrially not viable.

U.S. patent number 3,681,346 discloses the process for the preparation of Flupentixol Decanoate; the compound represented by structural formula (I) comprises, treatment of alpha isomer of the compound represented by structural formula (II) with acid chloride of decanoic acid in acetone, reflux then dry hydrogen chloride in ether, treated with aqueous ammonia to obtain decanoic acid ester of the alpha isomer of the compound represented by structural formula (I). Process of this patent is carried out at comparatively high temperature providing low yields and isomeric purity is not disclosed. Further it has been discussed that if the decanoate is obtained as a mixture of isomers, the alpha isomer is isolated by fractional crystallization.
United Kingdom patent number GB925538 discloses generically the resolution of the two isomers of Flupentixol; the compound represented by structural formula (II) by the fractional crystallization of the dihydrochloride salt of the compound represented by structural formula (II). However, such resolution is not industrially viable.
European patent number 1,673,365 discloses the resolution of E isomer and Z isomer of Flupentixol, the compound represented by structural formula (II) by formation of its p-chlorobenzoate ester hydrochloride salt followed by treatment with base to obtain Z-Flupentixol which is further converted into Z-Flupentixol decanoate; the compound represented by structural formula (I) at around 40-70 °C having yield of 94% and isomeric purity of 85% of Z isomer. Process of this patent is having multiple steps and carried out comparatively high temperature providing low isomeric purity of Z isomer.
Prior art processes are having multiple steps and carried out comparatively high temperature providing low yields and low isomeric purity of Z isomer. This is not economically and industrially viable.
Accordingly, there is a need in the art to develop process for resolution of Z and E isomers of Flupentixol; the compound of structural formula (II) which is simple, economic, safe and industrially viable providing substantially pure Z isomer the

compound of structural formula (II) which can be further used for the synthesis of the Z-Flupentixol decanoate; the compound represented by structural formula (I).
Accordingly, present invention provides process for resolution of E & Z isomers of Flupentixol by formation of mandelate salt of Flupentixol which can further used for the preparation of Z-Flupentixol decanoate.
Object of the invention:
i) An object of the present invention is to provide a new, simple, economic,
safe and industrially viable process for the preparation of Z isomer Flupentixol decanoate; the compound represented by structural formula (I) with high isomeric purity.
ii) Another object of present invention is to provide a process for the resolution of Flupentixol; the compound represented by structural formula (II) containing the mixture of E isomer and Z isomer using mandelic acid to obtain mandelate salt of Z-Flupentixol which can be further used for the synthesis of (Z) isomer of Flupentixol decanoate; the compound represented by structural formula (I).
Summary of the invention:
According to an aspect of the present invention is to provide a process for resolution of Flupentixol; the compound represented by structural formula (II) containing a mixture of E and Z isomer;

Comprises,

a) reacting Flupentixol; the compound represented by structural formula (II) containing a mixture of E and Z isomer with (R and S) mandelic acid in an organic solvent to obtain mandelate salt of (Z) isomer of the compound of formula (II);

b) treating mandelate salt of Z isomer of the compound of formula (II) with aqueous base in a solvent to obtain Z isomer the compound of formula (II);

c) The aspect of present invention is to use compound of formula III as salt forming agent are selected from Mandelic acid and its derivatives. Preferably salt forming agent is S (+)-mandelic acid. Said derivatives of the mandelic acid are selected from corresponds of formula III.


Compound of formula III represent mandelic acid and its derivatives like halogens, alkyl, alkoxyl, acetyl, benzoyl, nitrite, nitro and amine substituted at any position.
d) optionally, reacting Z isomer of the compound of formula (II) with a decanoyl chloride in presence of a base in an organic solvent to obtain the compound represented by structural formula (I) in pure (Z) form;

e) optionally, reacting the compound represented by structural formula (I) obtained in step (c) with (R and S) mandelic acid in solvent to obtain acid addition salt of Z isomer of the compound of structural formula (I); and
f) optionally, treating acid addition salt of Z isomer of the compound of formula (I) obtained in step (d) with aqueous base in a solvent to obtain Z isomer of the compound of formula (I).
Detailed description of the invention:
According to the present invention to provide a process for resolution of Flupentixol; the compound represented by structural formula (II) containing a mixture of E and Z isomer


Comprises,
a) reacting Flupentixol; the compound represented by structural formula (II) containing a mixture of E and Z isomer with mandelic acid (R and S) and its derivatives are used as salt forming agent for the separation of Z isomer in an organic solvent to obtain mandelate salt of the compound of formula (II);

b) treating mandelate salt of Z isomer of the compound of formula (II) with aqueous base in an organic solvent to obtain Z isomer of the compound of structural formula (II);


c) optionally, reacting Z isomer of the compound of formula (II) with a decanoyl chloride in presence of a base in an organic solvent to obtain the compound represented by structural formula (I) in pure (Z) form;

d) optionally, reacting the compound represented by structural formula (I) obtained in step c) with (R and S) mandelic acid in solvent to obtain acid addition salt of Z isomer of the compound of formula (I); and
e) optionally, treating acid addition salt of Z isomer of the compound of formula (I) obtained in step d) with aqueous base in a solvent to obtain Z isomer of the compound of formula (I).
In an embodiment of the present invention resolution of E/Z mixture of the compound represented by structural formula (II) is carried out in the step a) using (R and S) mandelic acid in an organic solvent to obtain mandelate salt of (Z) isomer of the compound represented by structural formula (II).
In accordance with an embodiment of the present invention the organic solvent used in the steps a) is selected from group consisting of ketone, hydrocarbon and ether.
In the specific embodiment of the present invention the organic solvent used in the steps a) is acetone, toluene and ethyl acetate.

In accordance with an embodiment of the present invention the mandelate salt of the Z-isomer of the compound of formula (II) can be isolated by filtration wherein, Z-isomer is isolated as solid while E-isomer goes in mother liquor.
In another embodiment of the present invention; in the step b); the mandelate salt of (Z) isomer of the compound of formula (II) treated with base in an organic solvent to obtain Z isomer of the compound represented by structural formula (II).
In accordance with another embodiment of the present invention; the organic solvent used in the step (b) is selected from the group consisting of ketone, hydrocarbon and ether.
In the specific embodiment of the present invention the organic solvent used in the steps b) is toluene.
In accordance with another embodiment of the present invention the base used in the step (b) is selected from the group consisting of amines, alkali metal carbonates, alkali metal bicarbonates.
In the specific embodiment of the present invention the base used in the step (b) is sodium bicarbonate or potassium carbonate.
In another embodiment of the present invention; in the step c); optionally Z isomer of the compound represented by structural formula (II) reacted with a decanoyl chloride in presence of a base in an organic solvent to obtain the compound represented by structural formula (I) in pure Z form.

In accordance with another embodiment of the present invention; the organic solvent used in the step (c) is selected from the group consisting of ketone, hydrocarbon and ether.
In the specific embodiment of the present invention the organic solvent used in the steps (c) is toluene.
In accordance with another embodiment of the present invention the aqueous base used in the step (c) is selected from the group consisting of amines, alkali metal carbonates, alkali metal bicarbonates
In the specific embodiment of the present invention the aqueous base used in the step (c) is Triethylamine.
In accordance with another embodiment of the present invention the organic solvent used in the step (d) is selected from group consisting of alcohol such as methanol and isopropanol.
In another embodiment of the present invention; in the step e); acid addition salt of Z isomer of the compound of formula (I) obtained in step (d) further treated optionally with aqueous base in a solvent to obtain a compound of formula (I).
In accordance with another embodiment of the present invention the organic solvent used in the step (e) is selected from group consisting of ketone, hydrocarbon and ether. In accordance with another embodiment of the present invention the aqueous base used in the step (e) is selected from the group consisting of amines, alkali metal carbonates, alkali metal bicarbonates.

In the specific embodiment of the present invention the aqueous base used in the step (e) is sodium bicarbonate or potassium carbonate.
In accordance with another embodiment of the present invention the organic solvent used in the step (e) is selected from group consisting of ether such as tert-butyl methyl ether (MTBE).
In another embodiment of the present invention; wherein reaction performed in step (a), (b), (c), (d) and (e) is carried out at a temperature below 35°C.
Examples:
The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.
Example: 1. Preparation of Flupentixol mandelate
Flupentixol 100 g (0.230 mol, 45% Z-isomer and 55% E-isomer) was dissolved in acetone (800 mL) under stirring to get clear solution, followed by addition of S-(+)-mandelic acid (45 g, 0.296) in one lot. This mixture was stirred for 3-4 hours at 25-30°C. Solid formation was observed. Solid was filtered and wash with acetone (100 mL) further crystallized in methanol. Solid was filtered and dried.
Yield: 62 g.
Isomeric purity: 99.8% Z-isomer and 0.2% E-isomer (By HPLC method).
Example: 2. Preparation of Flupentixol mandelate
Flupentixol 100 g (0.230 mol, 42% Z-isomer and 58% E-isomer) was dissolved in toluene (900 mL) under stirring. To get clear solution, followed by addition of R-(-)-

mandelic acid (45 g, 0.296) at 25-30°C. This mixture was stirred for 3-4 hours at 25-30°C. Solid formation was observed. Solid was filtered and wash with toluene (100 mL) and further crystallized in methanol. Solid was filtered and dried.
Yield: 50 g.
Isomeric purity: 99.4% Z-isomer and 0.6% E-isomer (By HPLC method).
Example: 3. Preparation of Flupentixol mandelate
Flupentixol 100 g (0.230 mol, 47% Z-isomer and 53% E-isomer) was dissolved in ethyl acetate under stirring to get clear solution, followed by addition of S-(+)-mandeIic acid (45 g, 0.296). This mixture was stirred for 3-4 hours at 25-30°C temperature. Solid formation was observed. Solid was filtered and wash with ethyl acetate (100 mL) further crystallized in methanol. Solid was filtered and dried.
Yield: 61 g.
Isomeric purity: 99.9% Z-isomer and 0.1% E-isomer (By HPLC method).
Example: 4. Preparation of Flupentixol
Flupentixol mandelate 50 g (99.8% Z-isomer and 0.2% E-isomer) obtained from above example (1) was suspended in toluene (400 mL) under stirring followed by pH adjustment by using aqueous solution of sodium bicarbonate until the aqueous phase was basic (pH= 8.0 to 9.0). The reaction mixture was stirred at 25-30°C temperature to get clear solution. The organic phase was separated out and aqueous phases extracted with toluene (200 mL). The organic phases were combined and washed with water (500 mL), then dried with anhydrous sodium sulfate, filtered and evaporated to dryness.
Yield: 32 g.

Isomeric purity: 99.8% Z-isomer and 0.2% E-isomer (By HPLC method).
Example: 5. Preparation of Flupentixol Decanoate
Flupentixol 32 g (99.8% Z-isomer and 0.2% E-isomer) obtained from above example (4) was dissolved in toluene (400 mL) under stirring followed addition of Triethyl amine (35 g, 0.345 mol) at 20-30°C. Decanoyl chloride (32.9 g, 0.173 mol) was added at 20-30°C. Progress of reaction was monitored by thin layer chromatography (TLC). After completion of reaction, water (500 mL) was added in reaction mixture. pH of reaction mixture was adjusted 8.0-9.0 by using Sodium bicarbonate solution. The organic phases were separated out and aqueous phases extracted with toluene (200 mL). The organic extracts were combined and washed with water (400 mL), then dried with anhydrous sodium sulfate, filtered and evaporated to dryness to get yellow viscous oil as Flupentixol decanoate.
Yield=38g.
Isomeric purity: 99.8% Z-isomer and 0.2% E-isomer (By HPLC method).
Example: 6. Preparation of Flupentixol Decanoate dihydrochloride
Flupentixol 50 g (99.8% Z-isomer and 0.2% E-isomer) was dissolved in toluene (400 mL) under stirring followed addition of Triethyl amine (35 gm, 0.345 mol) at 25-30°C. Decanoyl chloride (32.9 g, 0.173 mol) was added at 25-30°C. Progress of reaction was monitored by thin layer chromatography (TLC). After completion of reaction, water (600 mL) was added in reaction mixture. pH of reaction mixture was adjusted 8.0-9.0 ■ by using Sodium carbonate solution. The organic phases were separated out and aqueous phases extracted with toluene (200 mL). The organic extracts were combined and washed with water (400 mL), then dried with anhydrous sodium sulfate, filtered.

IPA. HC1 (28 mL) was added drop-wise at 25-30°C until pH 1-2 in toluene layer. Solid was precipitated but and reaction mixture was stirred at 25-30°C for 30 min. Solid was filtered and washed with toluene. Flupentixol Decanoate dihydrochloride was dried under vacuum. The yield was 64 g.
Isomeric purity: 99.8% Z-isomer and 0.2% E-isomer (By HPLC method).
Example: 7. Preparation of Flupentixol Decanoate dimaleate
Flupentixol mandelate 50 g (99.4% Z-isomer and 0.6% E-isomer) obtained from above example (2) was suspended in toluene (400 mL) under stirring followed by pH adjustment by using aqueous solution of sodium bicarbonate until the aqueous phase was basic (pH= 8.0 to 9.0). The reaction mixture was stirred at 25-30°C temperature to get clear solution. The organic phase was separated out and aqueous phases extracted with toluene (200 mL). The organic phases were combined and washed with water (400 mL), then dried with anhydrous sodium sulfate and filtered. To a solution of Z-Flupentixol in toluene, Triethyl amine (35 g, 0.345 mol) was added at 20-30°C. Decanoyl chloride (32.9 g, 0.173 mol) was added at 20-30°C temperature. Progress of reaction was monitored by thin layer chromatography (TLC). After completion of reaction, water (500 mL) was added in reaction mixture. pH of reaction mixture was adjusted 8.0-9.0 by using sodium bicarbonate solution. The organic phases were separated out and aqueous phases extracted with toluene (100 mL). The organic extracts were combined and washed with water (400 mL), then dried with anhydrous sodium sulfate, filtered and evaporated to dryness to get yellow viscous oil as Flupentixol decanoate. To the reaction mass methanol (500 mL) and maleic acid (21 g, 0.180 mol) was added at 45-50°C. Solid was filtered and washed with methanol. Flupentixol Decanoate dimaleate was dried under vacuum. The yield was 42 g.
Isomeric purity: 99.4% Z-isomer and 0.6% E-isomer (By HPLC method).

Example: 8. Preparation of Flupentixol Decanoate
Flupentixol Decanoate dimaleate, 40 g (99.4% Z-isomer and 0.6% E-isomer) obtained from above example (7) was dissolved in MTBE (400 mL) under stirring followed by adjustment of pH of reaction mixture was 8.0-9.0 by using Sodium bicarbonate solution. The organic phases were separated out and aqueous phases extracted with MTBE (200 mL). The organic extracts were combined and washed with water (400 mL), then dried with anhydrous sodium sulfate, filtered and evaporated to dryness under vacuum to get yellow viscous oil as Flupentixol decanoate. The yield was 26 g.
Isomeric purity: 99.4% Z-isomer and 0.6% E-isomer (By HPLC method).

We claim:
1. A process for resolution of Flupentixol; the compound represented by structural formula (II) containing the mixture of E and Z isomer

comprising,
a) reacting E/Z mixture of the compound of formula (II) with (R and S) mandelic acid in an organic solvent to obtain mandelate salt of the compound of formula (II);

b) treating mandelate salt of the compound represented by structural formula (II) with aqueous base in an organic solvent to obtain Z isomer of the compound of formula (II);


c) optionally, reacting Z isomer of the compound of structural formula (II) with a decanoyl chloride in presence of a base in an organic solvent to obtain the compound represented by structural formula (I);

d) optionally, reacting the compound represented by structural formula (I) obtained in step c) with acid in solvent to obtain acid addition salt of Z isomer of the compound represented by structural formula (I); and
e) optionally, treating acid addition salt of Z isomer of the compound of formula (I) obtained in step d) with aqueous base in a solvent to obtain Z isomer of a compound of formula (I).

2. The process as claimed in claim 1 wherein, the organic solvent used for step a), b) and c), is selected from acetone, toluene and ethyl acetate.
3. The process as claimed in claim 1 wherein, the organic solvent used in the step (d) is selected from methanol, isopropanol.
4. The process as claimed in claim 1 wherein, the solvent used for steps (e) is tert-butyl methyl ether (MTBE).
5. The process as claimed in claim 1 wherein, the base used for step (b) and (e) is selected from sodium bicarbonate and potassium carbonate.

6. The process as claimed in claim 1 wherein, the base used for step (c) is Triethylamine.
7. The process as claimed in claim 1 wherein, the acid used for steps (d) is Hydrochloric acid and maleic acid.
8. The process as claimed in claim I wherein, step (a), (b), (c), (d) and (e) is carried out at a temperature below 35°C.