Field of Invention
The novel method related to preparation of pure Zuclopenthixol using mandelic acid by formation of mandelate salt. The method comprises dissolving a mixture of E and Z-Clopenthixol into an organic solvent, added mandelic acid to form mandelate salt, crystallized in organic solvent, subsequently carrying out alkali hydrolysis to obtain pure Zuclopenthixol. The said process results in to Zuclopenthixol having excellent purity and good yield without involving multiple crystallization steps. The invention further relates to preparation of a carboxylic ester and pharmaceutically acceptable salt of Zuclopenthixol.

Background of the Invention
Zuclopenthixol is a typical antipsychotic drug of the thioxanthene class. It is typical antipsychotic agent and also used in the treatment of acute bipolar mania. It is the c/'s-isomer of Clopenthixol (Zuclopenthixol). Zuclopenthixol is chemically known as 4-[(3Z)-3-(2-Chloro-9H-thioxanthen-9-ylidene)propyl]-1-piperazine ethanol and is represented by structural Formula (I).
Zuclopenthixol is available in three different form
• As Zuclopenthixol acetate (Acuphase, Cisordinol-Acutard), it is a shorter acting intramuscular injection used in the acute sedation of psychotic inpatients. The effect peaks at 48-72 hours providing 2-3 days of sedation.
• Zuclopenthixol decanoate is a long acting intramuscular injection given every two or three weeks to people with schizophrenia who have a poor compliance with medication and suffer frequent relapses of illness. There is some evidence it may be more helpful in managing aggressive behaviour.
• Zuclopenthixol dihydrochloride is a tablet used in the treatment of schizophrenia in those who are compliant with oral medication.
As a long acting injection, Zuclopenthixol decanoate comes in a 200 mg and 500 mg ampoule. Doses can vary from 50 mg weekly to the maximum licensed dose of 600 mg weekly. In general, the lowest effective dose to prevent relapse is preferred. The interval may be shorter as a patient starts on the medication before extending to 3 weekly intervals subsequently.
In acutely psychotic and agitated inpatients, 50 - 200 mg of Zuclopenthixol acetate may be given for a calming effect over the subsequent three days, with a maximum dose of 400 mg in total to be given. As it is a long-acting medication, care must be taken not to give an excessive

dose. In oral form Zuclopenthixol is available in 10, 25 and 40 mg tablets, with a dose range of 20-60 mg daily.
When Clopenthixol is prepared according to the method described in US Patent No. 3,116,291 a mixture of isomers is obtained wherein approximately 35%, mostly about 30-50%, of the most active isomer (for convenience called alpha-clopenthixol) is present.
A separation of the isomers along the lines described in US Patent No. 3,116,291 failed to succeed. When fractional crystallization of either of free base or an acid addition salt thereof in various solvents was attempted the inactive beta-isomerbeing the most insoluble always crystallized out first, and from the mother liquors resulting from the crystallization only mixtures of the alpha- and beta-isomers were obtained.
US Patent No. 3,996,211 relates to the novel alpha-isomer of 2-Chloro-9-[3'-(N'-2-hydroxyethylpiperazino-N)-propylidene]-thiaxanthene carboxylic acid esters thereof, the non¬toxic acid addition salts of these compounds, methods of preparing and purifying the said compounds, therapeutic compositions thereof and a method of treating psychotic patients therewith. The draw-back of this process is during alkaline hydrolysis of ester of Zuclopenthixol, the acid is trapped with Zuclopenthixol as an impurity and removal of this impurity from Zuclopenthixol is very difficult and finally gives low yield with impurity.
Similarly CN103214453 relates to an improved method for separating and purifying Zuclopenthixol. The method comprises the specific steps of dissolving a mixture of an alpha-isomer (i.e. Zuclopenthixol) and a beta-isomer of Clopenthixol in to an organic solvent, adding an active benzoic acid derivative, and esterifying with the mixture so as to remove the beta-isomer; subsequently carrying out alkali hydrolysis on the residual substances so as to obtain relatively pure Zuclopenthixol; and further recrystallizing by using organic solvent. In addition, the invention further relates to preparation of a carboxylic esters and pharmaceutically acceptable acid salts of Zuclopenthixol.
None of the prior art directly or indirectly provides the improved process for preparation of pure Zuclopenthixol from isomeric mixture comprising mixture of E/Z-isomer. The present invention have skillfully developed a simple and efficient process for obtaining pure Zuclopenthixol.

Summary of the Invention
The first aspect of present invention is to provide efficient process for the preparation of pure Zuclopenthixol and pharmaceutically acceptable salts thereof with higher Z-isomeric purity and good yield. The process disclosed herein is industrially safe, economical and simple to manufacture pure Zuclopenthixol and its salts.
Similarly second aspect of present invention, there is provided a process for obtaining pure Zuclopenthixol comprising; treating Clopenthixol isomeric mixture of E and Z-isomer, with mandelic acid 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 Z-isomer of Zuclopenthixol mandelate as represented by structural formula II.
The third aspect of present invention is to provide Z-isomer Clopenthixol mandelate of formula II is chemically known as (Z)-2-4-[3-(2-Chlorothioxanthene-9-ylidene)propyl]piperazin-1-ylethanolmendelatewith optical purity of about 99%.
The fourth aspect of present invention is to use compound of formula III as salt forming agent preferably where R is H.

Compound of formula III represent mandelic acid and its derivatives.
X is halogens, alkyl, alkoxyl, acetyl, benzoyl, nitrile, nitro and amine substituted at any position. The fifth aspect of present invention is to provide a novel method for preparation of pure Zuclopenthixol of the formula I.
The sixth aspect of present invention is to provide a novel method for preparation of pure Zuclopenthixol acetate of the formula IV.
Detailed Description of the Invention
According to an aspect of present invention, there is provided a process for obtaining pure Zuclopenthixol comprising; treating Clopenthixol isomeric mixture containing E and Z-isomer, with Mandelic acid in organic solvent at.temperature ranging from 0 to 120°C.

More particularly, there is provided a process where in mixture of E and Z-Clopenthixol is subjected to treatment in organic solvent at a temperature ranging from 0 to 120°C till a clear solution obtained. This is followed by addition of salt forming agent of formula III preferably where R is H under the stirring and maintaining temperature at 0 to 120°C in organic solvent. (Z)-Zuclopenthixol mandelate is precipitated completely, filtered off and washed with organic solvent.
The specific embodiments of the present invention, Mandelic acid (racemic or R and S) and its derivatives are used as salt forming agent for the separation of Z-Clopenthixol (Zuclopenthixol) as depicted in the following scheme representations.
(Z)-Clopenthixol mandelate is precipitated out in organic solvent by reacting with mandelic acid and its derivative while (E)-Glopenthixol mandelate goes into mother liquor herein after referred as MLR.
The salt forming agents 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.

R is H, unsubstituted or substituted benzoyl Compound of formula III represent mandelic acid and its derivatives.
X is halogens, alkyl, alkoxyl, acetyl, benzoyl, nitrile, nitro and amine substituted at any position. According to an another aspect of present invention, there is provided a process for obtaining pure Z-Clopenthixol;
a) treating Clopenthixol isomeric mixture of E and Z-isomer, with a mandelic acid in organic solvent at a temperature ranging from 0°C to 120°C;
b) isolation and crystallization of Z-isomerof Clopenthixol mandelate salt in polar and non-polar organic solvent;
c) basification of Z-isomer of Clopenthixol mandelate salt by using base in water, organic solvent and mixture thereof;
d) washing the organic layer obtained in step c) by water and concentrate the organic layer under reduced pressure to obtained residue ofZuclopenthixol;
e) Zuclopenthixol is dissolved in aromatic and chlorinated solvent, added base and acetyl chloride at 0 to 25°C temperature to convert in Zuclopenthixol acetate;
f) Zuclopenthixol acetate is dissolved in organic solvents followed by addition of IPA. HCI to obtained Zuclopenthixol acetate dihydrochloride.
g) Zuclopenthixol acetate dihydrochloride is dissolved in water and organic solvents, adjust pH 8 to 9 with base.
h) Treating the obtained product in step g) by base to obtain the pure Zuclopenthixol acetate as yellowish viscous oil.

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 C1 -C7 alkoxide such as sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or lithium methoxides.
The example of organic base include but not limited to triethylamine, diisopropylamines, imidazole, pyridine, pyridazine, pyrimidine, lithium diisopropylamide, potassium tert-butoxide, dimethyl amino pyridine, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) and mixture(s) thereof.
The organic solvent used in the second embodiment of salt preparation is selected from non-polar or polar solvent. The example of non-polar organic solvent may include but not limited to chloroform, toluene, benzene,diethyl ether, methyl tert. butyl ether (MTBE), pentane, cyclopentane, hexane, cyclohexane of mixture(s) 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 or ketonic solvent such as acetone, ethyl ketone, methyl ethyl ketone and mixtures thereof. Preferably solvent is selected from the group containing acetone, toluene, isopropanol, ethyl acetate, methyl tert butyl ether and mixture(s) thereof.
The amount of solvent used with respect to isomeric mixture of Clopenthixol used as starting material is in range of 5 to 20 volumes. The molar ratio of Mandelic acid or its derivatives more preferably mandelic acid used with respect to E/Z isomeric mixture of Clopenthixol used as starting material is in range of 0.9 to 2.5
According to an embodiment of present invention, the process provides pure Zuclopenthixol acetate at temperature range 0 to 25°C.
According to present invention, for isolation of pure Z-isomer of Clopenthixol from Clopenthixol isomeric mixture of E and Z-isomer, the solvent system and proper acid for selectivity plays a vital role wherein the innovators of the present invention skillfully designed the combination of solvent system and selective acid 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 purity were obtained by high performance liquid chromatography (HPLC) analysis.

EXAMPLE
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example: 1.Preparation of Zuclopenthixol mandelate salt
10 gm (0.0249 mol, 40% Z-isomer and 60% E-isomer) Clopenthixol was dissolved in acetone (80 ml) under stirring. To get clear solution, followed by addition of S(+)-mandelic acid (4.5 g, 0.0296) in one lot. This mixture was stirred for 4 hours at 25-30°C temperature. Solid formation was observed. Solid was filtered and wash with acetone (10 ml) further crystallized in methanol. Solid was filtered and dried.
Yield: 12.4 gm.
Isomeric purity: 99.6% Z-isomer and 0.4% E-isomer (By HPLC method)
Example: 2.Preparationof Zuclopenthixol mandelate salt
10 gm (0.0249 mol, 40% Z-isomer and 60% E-isomer) Clopenthixol was dissolved in toluene (90 ml) under stirring. To get clear solution, followed by addition of S(+)-mandelic acid (4.5 g, 0.0296) in one lot. This mixture was stirred for 4 hours at 25-30°C temperature. Solid formation was observed. Solid was filtered and wash with toluene (10 ml) further crystallized in methanol. Solid was filtered and dried.
Yield: 14.8 gm.
Isomeric purity: 99.5% Z-isomer and 0.5% E-isomer (By HPLC method).
Example: 3.Preparation of Zuclopenthixol mandelate salt
10 gm (0.0249 mol, 40% Z-isomer and 60% E-isomer) Clopenthixol was dissolved in ethyl acetate and methyl tert. butyl ether (MTBE) (100 ml) under stirring. To get clear solution, followed by addition of S(+)-mandelic acid (4.5 g, 0.0296). This mixture was stirred for 4 hours

at 25-30°C temperature. Solid formation was observed. Solid was filtered and wash with ethyl acetate and methyl tert. butyl ether (10 ml) further crystallized in methanol. Solid was filtered and dried.
Yield: 14.0 gm.
Isomeric purity: 99.7% Z-isomer and 0.3% E-isomer (By HPLC method).
Example: 4.Preparation of Zuclopenthixol
10 gm (99.6% Z-isomer and 0.4% E-isomer) Zuclopenthixol mandelate salt obtained from above examples was suspended in toluene (40 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 (20 ml). The organic phases were combined and washed with water (50 ml), then dried with anhydrous sodium sulfate, filtered and evaporated to dryness.
Yield: 7.6 gm.
Isomeric purity: 99.60% Z-isomer and 0.4% E-isomer (By HPLC method).
Example: 5.Preparation of Zuclopenthixol acetate
5.0 gm (99.6% Z-isomer and 0.4% E-isomer) Zuclopenthixol obtained from above example was dissolved in toluene (40 ml) under stirring followed addition of triethyl amine (2.0 gm, 0.019 mol) at 0-5°C. Acetyl chloride (1.6 gm, 0.020 mol) was added at 0-5°C temperature. Progress of reaction was monitored by thin layer chromatography (TLC). After completion of reaction, water (50 ml) was added in reaction mixture. The organic phases was separated out and aqueous phases extracted with toluene (20 ml). The organic extracts were combined and washed with water (40 ml), then dried with anhydrous sodium sulfate, filtered and evaporated to dryness to get oil as Zuclopenthixol acetate.
Yield= 5.0 gm.

Isomeric purity: 99.6% Z-isomer and 0.4% E-isomer (By HPLC method).
Example: 6.Preparation of Zuclopenthixol acetate dihydrochloride
5.0 gm (99.6% Z-isomer and 0.4% E-isomer) Zuclopenthixol acetate obtained from above example was dissolved in acetone (50 ml) under stirring followed drop-wise addition of IPA. HCI (2.8 ml) at 25-30°C until pH 1-2. Solid was precipitated out and reaction mixture was stirred at 25-30°C for 30 min. Solid was filtered and washed with acetone. Zuclopenthixol acetate dihydrochloride was dried under vacuum. The yield was 4.2 gm.
Isomeric purity: 99.8% Z-isomer and 0.2% E-isomer (By HPLC method).
Example: 7.Preparation of Zuclopenthixol acetate dihydrochloride
5.0 gm (99.6% Z-isomer and 0.4% E-isomer) Zuclopenthixol obtained from above example was dissolved in toluene (40 ml) under stirring followed addition of triethyl amine (2.0 gm, 0.019 mol) at 0-5°C. Acetyl chloride (1.6 gm, 0.020 mol) was added at 0-5°C temperature. Progress of reaction was monitored by thin layer chromatography (TLC). After completion of reaction, water (50 ml) was added in reaction mixture. The organic phase was separated out and aqueous phases extracted with toluene (20 ml). The organic phases were combined and washed with water (40 ml), then dried with anhydrous sodium sulfate, filtered, evaporated to dryness and dissolved in acetone (50 ml) under stirring followed drop-wise addition of IPA. HCI (2.8 ml) at 25-30°C until pH 1-2. Solid was precipitated out and reaction mixture was stirred at 25-30°C for 30 min. Solid was filtered and washed with acetone. Zuclopenthixol acetate dihydrochloride was dried under vacuum. The yield was 4.0 gm.
Isomeric purity: 99.7% Z-isomer and 0.3% E-isomer (By HPLC method).

We claim:
1. A novel compound (Z)-Zuclopenthixol mandelate salt of the formula II.
2. Process for preparation of (Z)-Zuclopenthixol mandelate salt formula II comprising;
a) treating Clopenthixol isomeric mixture of E-isomer and Z-isomer, with a mandelic acid in organic solvent at a temperature ranging from 0°C to 120°C;
b) isolation and crystallization of Z-isomerof Clopenthixol mandelate salt in polar and non-polar organic solvent;
c) basificationof Z-isomerof Clopenthixol mandelate salt by using base in water, organic solvent and mixture thereof;
d) washing the organic layer obtained in step c) by water and concentrate the organic layer under reduced pressure to obtained residue of Zuclopenthixol;
e) Zuclopenthixol is dissolved in aromatic and chlorinated solvent, added base and acetyl chloride at 0 to 25°C temperature to convert in Zuclopenthixol acetate;
f) Zuclopenthixol acetate is dissolved in organic solvents followed by addition of IPA. HCI to obtained Zuclopenthixol acetate dihydrochloride.
g) Zuclopenthixol acetate dihydrochloride is dissolved in water and organic solvents, adjust pH 8-9 with base.
h) Treating the obtained product in step g) by base to obtain the pure Zuclopenthixol acetate as yellowish viscous oil.
3. A process as claimed in claim 2, wherein isomeric mixture of Clopenthixolis subjected to
treatment with a mendelic acid and its derivatives in organic solvent and converted in to
pure Zuclopenthixol as represented by structural formula I.

4. The processes as claimed in claim 2, the salt forming agents are selected from Mandelic acid and its derivatives. Preferably salt forming agent is mandelic acid. Said derivatives of the mandelic acid are selected from corresponds of formula III. The molar ratio of Mandelic acid or its derivatives more preferably mandelic acid used with respect to E/Z isomeric mixture of Clopenthixol used as starting material is in range of 0.9 to 2.5
R is H, unsubstituted or substituted benzoyl Compound of formula III represent mandelic acid and its derivatives.
X is halogens, alkyl, alkoxyl, acetyl, benzoyl, nitrile, nitro and amine substituted at any position. 5. The process as claimed in claim 2, to provide a novel method for preparation of pure Zuclopenthixol acetate of the formula IV.

6. The process as claimed in claim 2, 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 C1 -C7 alkoxide, such as sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or lithium methoxides. The example of organic base include but not limited to triethylamine, diisopropylamines, imidazole, pyridine, pyridazine, pyrimidine, lithium diisopropylamide, potassium tert-butoxide, dimethyl amino pyridine, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) and mixture(s) thereof..
7. The process as claimed in claim 2, the organic solvent used is selected from non-polar or polar solvent. The example of non-polar organic solvent may include but not limited to chloroform, toluene, benzene, diethyl ether, methyl tertbutyl ether (MTBE), pentane, cyclopentane, hexane, cyclohexane of mixture(s) thereof.
8. The process as claimed in claim 2, 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 or ketonic solvent such as acetone, ethyl ketone, methyl ethyl ketone and mixtures thereof. Preferably solvent is selected from the group containing acetone, toluene, isopropanol, ethyl acetate, methyl tert butyl ether and mixture(s) thereof.
9. The process as claimed in claim 2, the amount of solvent used with respect to isomeric mixture of Zuclopenthixol used as starting material is in range of 5 to 20 volumes.
10. The process as claimed in claim 2, crystallization in organic protic and aprotic solvents used with respect to 1 to 15 volumes.