FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of Fluphenazine dihydrochloride (1) with purity greater than 99.0%. It further, relates to a process for the purification of Fluphenazine dihydrochloride (1).
BACKGROUND OF THE INVENTION
Fluphenazine is an antipsychotic drug used for the treatment of schizophrenia. It is chemically known as 2-(4-(3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl) propyl) piperazin-l-yl)ethanol and marketed by Schering-Plough corporation under the brand name permitil.
The following patents describes the synthesis of Fluphenazine dihydrochloride (1), the contents of which are hereby incorporated as reference in their entirety.
US3058979 discloses process for the preparation of Fluphenazine dihydrochloride (1) by condensing the compound (5) with compound (7) to form intermediate compound (8). The intermediate compound (8) on reduction with reducing agent to form intermediate (9). Next condensing of intermediate compound (9) with compound (10) to result intermediate compound (11). The obtained intermediate compound (11) on hydrolysis by using acid to form fluphenazine free base (12). Finally, the free base (12) is converted to its hydrochloride salt (1) by treating with alcoholic hydrogen chloride.
The process described above is not industrially viable due to it involves a greater number of steps and purification of each step results low yield of final compound. And the process does not report the yield and degree of purity of the compounds obtained.

To overcome the drawbacks associated with the prior art the present inventors hereby report an improved process for the preparation of Fluphenazine dihydrochloride (1) in less steps with better yield and greater purity.
OBJECTIVE OF THE INVENTION
Accordingly, one objective of the present invention is to novel process for the preparation of Fluphenazine dihydrochloride (1).
Another objective of the present invention is to provide a process for the purification of Fluphenazine dihydrochloride (1).
Yet, another objective of the present invention is to provide a process for limiting the impurities coupled with products of the respective stage.
Yet, another objective of the present invention is to provide Fluphenazine dihydrochloride (1) with purity greater than 99% by High-performance liquid chromatography (HPLC).

SUMMARY OF THE INVENTION
Accordingly, in one aspect, the present invention provides novel process for the preparation of Fluphenazine dihydrochloride (1) with purity greater than 99.0%.
In another aspect, the steps involved in the preparation of Fluphenazine dihydrochloride (1) is as shown in scheme-1 are as follows:
a) reacting N-phenyl-3-(trifiuoromethyl) aniline (6) with sulphur and iodine to form N-phenyl-3-(trifluoromethyl)aniline (5);
b) condensing N-phenyl-3-(trifluoromethyl)aniline (5) with chlorobromoprop ane (4) to form 10-(3-chloropropyl)-2-(trifluoromethyl)-10H-phenothi azine (3); and
c) reacting 10-(3-chloropropyl)-2-(trifluoromethyl)-10H-phenothiazine (3) with 2-(piperazin-l-yl) ethanol (2) to form 2-(4-(3-(2-(trifiuoromethyl)-lOH-pheno thiazin-10-yl) propyl) piperazin-l-yl)ethanol dihydrochloride (1)-
In another aspect the present invention provides process for the preparation of intermediate compounds N-phenyl-3-(trifluoromethyl)aniline (6) and 2-(piperazin-1-yl) ethanol (2).
In another aspect the present invention provides process for the purification of Fluphenazine dihydrochloride (1) comprising of
i. providing a solution of Fluphenazine dihydrochloride (1) in a suitable protic solvent or mixtures thereof;
ii. heating the reaction mixture to a suitable temperature; iii. cooling the reaction mixture to a suitable temperature; iv. filtering the reaction mixture and adding suitable aprotic solvent; and
v. isolating pure Fluphenazine dihydrochloride (1)
Yet, another aspect of the present invention is to provide pure Fluphenazine dihydrochloride (1) with purity greater than 99% by High-performance liquid chromatography (HPLC).

In yet, another objective of the present invention Fluphenazine dihydrochloride (1) obtained after purification is having impurities less than 1.0% (w/w), preferably less than 0.5%.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1: illustrates the X-Ray powder diffraction pattern (XRPD) of Fluphenazine
dihydrochloride (1).
DETAILED DESCRIPTION OF THE INVENTION
In one aspect the present invention provides an improved process for the synthesis of Fluphenazine dihydrochloride (1) with purity greater than 99% by HPLC as illustrated in scheme 2.

Step a) proceeds with reacting N-pheny 1-3-(trifluoromethyl)aniline (6) with sulphur and iodine to form 2-(trifluoromethyl)-10H-phenothiazine (5). The reaction may be carried out at a temperature of 130-160 °C preferably at 140-150 °C. On completion of the reaction, the reaction mixture was cooled to 95-100 °C and suitable aprotic solvent was added and stirred for 1 h. The reaction mixture was washed with a hot

aprotic solvent and further the reaction mixture was cooled and filtered. The obtained solid was washed with a suitable aprotic solvent and dried to afford pure 2-(trifluoromethyl)-10H-phenothiazine (5). The present invention provides process for the purification of 2-(trifluoromethyl)-10H-phenothiazine (5. using aprotic solvent preferably hexane. In another embodiment, the purification of 2-(trifluoromethyl)-lOH-phenothiazine (5) involves heating of crude in aprotic solvent at 50-55°C and cooling to 25-30°C to precipitate the solid.
Step b) proceeds with condensing 2-(trifluoromethyl)-10H-phenothiazine (5) with chlorobromopropane (4) in a suitable aprotic solvent and in the presence of suitable base and phase transfer catalyst to form 10-(3-chloropropyi)-2-(trifluoro methyl)-1 OH-phenothiazine (3). The reaction may be carried out at a temperature of 30-50 °C preferably at 40-50 °C and more preferably at 45-50 °C.
The suitable aprotic solvent used in step b) can be selected from the group comprising of dichloromethane, acetonitrile, Ethylacetate, tetrahydrofuran, toluene, cyclohexane, diethyl ether, methyl tertiary butyl ether or the like preferably acetonitrile was used in the present invention.
In another embodiment, the compound 10-(3-chloropropyl)-2-(trifluoro methyl)-1 OH-phenothiazine (3) can be used directly for the next stage, which makes it industrially viable. This is advantageous over prior art, as the number of purifications increases, the yield of the final compound may decrease.
Step c) proceeds with reacting 10-(3-chloropropyl)-2-(trifluoromethyl)-l OH-phenothiazine (3) with 2-(piperazin-l-yl)ethanol (2) in the presence of suitable base, suitable alkaline iodide and phase transfer catalyst to form 2-(4-(3-(2-(trifluoromethyl)-1 OH-phenothiazin-10-yl)propyl)piperazin-1 -yl)ethanol dihy dro chloride (1). The reaction may be carried out at a temperature of 70-90 °C, preferably at 80-90 °C and more preferably at 80-85 °C.
In the present invention the present inventors have reported the compound 2-(4-(3-
(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propyl)piperazin-l-yl)ethanol di
hydro chloride (1) with purity greater than 99%. In addition, the present invention

reported the formation of impurity 2-(4-(3-(2',8-bis(trifluoromethyl)-10H-[2,l 0'-biphenothiazin]-10-yl)propyl)piperazin-l-yl)ethanol along with the desired compound 2-(4-(3-(2-(trifiuoromethyl)-10H-phenothiazin-10-yl)propyl)piperazin-l-yl)ethanol dihydrochloride (1). Further the present invention discloses the purification method for the removal of impurities which is advantageous over prior art.
In another aspect the present invention provides process for the purification of Fluphenazine dihydrochloride (1) comprising of
i. providing a solution of Fluphenazine dihydrochloride (1) in a suitable protic solvent or mixtures thereof;
ii. heating the reaction mixture to a suitable temperature; iii. cooling the reaction mixture to a suitable temperature; iv. filtering the reaction mixture and adding suitable aprotic solvent; and
v. isolating pure Fluphenazine dihydrochloride (1)
The said purification can be carried out at a temperature of 50-70 °C preferably at 60-70 °C and more preferably at 60-65 °C.
The suitable protic solvents used in the present invention can be selected from the group consisting of but not limited to ethanol, methanol, isopropyl alcohol, water or the like preferably methanol was used in the present invention.
The suitable aprotic solvents used in the present invention can be selected from the group consisting of but not limited to ethyl acetate, tetrahydrofuran, dichloromethane, toluene, acetonitrile, cyclohexane, diethyl ether, methyl tertiary butyl ether or the like preferably toluene, cyclohexane, acetonitrile, methyl tertiary butyl ether were used in the present invention.
The suitable phase transfer catalyst used in the present invention can be selected from the group consisting of but not limited to tetrapropylammonium bromide, tetra butylammonium bromide, tributylbenzylammonium bromide, tetraoctyl ammonium bromide, tetrabutylammoniumhydrogen sulfate, benzyltriethyl

ammonium bromide, tetrabutylammonium acetate, tetrabutylammonium iodide or the like preferably tetrabutylammonium bromide was used in the present invention.
The suitable base used in the present invention can be selected from the group consisting of but not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium hydroxide, aqueous ammonia or the like preferably, potassium carbonate was used in the present invention.
The suitable alkaline halide used in the present invention can be selected from the group consisting of but not limited to sodium iodide, potassium iodide preferably potassium iodide was used in the present invention.
In another embodiment the present invention provides process for the preparation of N-phenyl-3-(trifluoromethyl)aniline (6) as shown in Scheme-3 comprising of;
1. reacting 3-(trifluoromethyl)aniline (15) with bromobenzene (14) in the
presence of suitable acid to form N-phenyl-N-(3-(trifluoromethyl)phenyl)
formamide (13);
2. reacting N-phenyl-N-(3-(trifluoromethyl)phenyl)formamide (13) with
copper carbonate and potassium carbonate followed by acid hydrolysis to
form N-phenyl-3-(trifluoromethyl)aniline (6).


In another embodiment the present invention provides process for the preparation of 2-(piperazin-l-yl) ethanol (2) as shown in scheme 4 by reacting piperazine (16) with oxirane (17) to form a mixture of 2-(piperazin-l-yl) ethanol (2) and 2,2'-(piperazine-l,4-diyl) diethanol (12) which on distillation yielded 2-(piperazin-l-yl) ethanol (2).

The suitable acid used in the present invention can be selected from the group comprising of hydrochloric acid, formic acid, hydrobromic acid, acetic acid and the like preferably hydrochloric acid, formic acid were used in the present invention.
The Fluphenazine dihydrochloride (1) obtained after purification was having purity greater than 99% by HPLC.
In one aspect, Fluphenazine dihydrochloride (1) obtained after purification is having total impurities less than 1.0%, preferably less than 0.5%.
In another aspect, Fluphenazine dihydrochloride (1) obtained after purification having impurity C represented as 2-(4-(3-(2',8-bis(trifluoromethyl)-10H-[2,10'-biphenothiazin]-10-yl)propyl)piperazin-l-yl)ethanol (impurity C) less than 0.15 %, preferably less than 0.05% .

In another aspect the present invention provides Fluphenazine dihydrochloride (1) having characteristic X-Ray powder diffraction is as shown in Figure-1, may have 2(9) values (±0.2) as tabulated in Table-1 below

The following examples further illustrate the present invention but should not be construed in any way as to limit its scope.
EXAMPLES
EXAMPLE 1 : Preparation of 2-(trifluoromethyl)-10H-phenothiazine (5)
To a mixture of 100 g of N-phenyl-3-(trifluoromethyl) aniline (6) and 27 g of sulphur, 2.67 g of iodine was added at 25-30 °C. The reaction mass was heated to 150-155 °C and stirred for 4 h. The reaction mixture was cooled to 90-95 °C, 500 mL of toluene was added and stirred for 1 h at 90-95 °C. The reaction mixture was filtered and washed with 50 mL of toluene. The obtained filtrate was cooled to 0-5 °C. The solid was heated in cyclohexane at 50-55°C and cooled to 25-30°C. The obtained solid was washed with cyclohexane and acetone then dried to afford 2-(trifluoromethyl)-lOH-phenothiazine (5). Yield: 33%, Purity: 95%.
EXAMPLE 2: Preparation of 10-(3-chloropropyl)-2-(trifluoromethyl)-10H-phenothiazine (3)
100 g of 2-(trifluoromethyl)-10H-phenothiazine (5) was dissolved in 500 mL of acetonitrile at 25-30 °C. 59.84 g of sodium hydroxide was added. To this 24.11 g of tetra butyl ammonium bromide and 70.69 g of chlorobromopropane (4) were added at 25-30 °C. The reaction mass was heated to 50-55 °C and stirred for 2-3 h at 50-55 °C. after completion of reaction, the reaction mixture was filtered to remove the solid. The solvent was removed from the filtrate under vacuum and degassed for 30 min at 45-50 °C to afford 10-(3-chloropropyl)-2-(trifluoromethyl)-1 OH-phenothiazine (3) which is directly used for next step without isolation.

EXAMPLE 3: Preparation of 2-(4-(3-(2-(trifIuoromethyl)-10H-phenothiazin-10-yl) propyl) piperazin-1-yl) ethanol dihydrochloride (Fluphenazine dihydrochloride) (1)
To 100 g of 10-(3-chloropropyl)-2-(trifluoromethyl)-10H-phenothiazine (3), 51.67 g of potassium carbonate and 62.1 g of potassium iodide were added at 25-30 °C. To the reaction mixture 73 g of 2-(piperazin-l-yl) ethanol (2) was added and heated to 80-85 °C, stirred for 12-13 h. After completion of the reaction, the reaction mass was filtered. The filtrate was distilled under reduced pressure and degassed to afford crude 2-(4-(3-(2-(trifluoromethyl)-1 OH-phenothiazin-10-yl) propyl)piperazin-1 -yl)ethanol. To this, 400 mL of toluene and 400 mL of 50% hydrochloric acid were added and stirred. The organic and aqueous layers were separated. The pH of the aqueous layer was adjusted to 7.5-8 by sodium carbonate solution. The product was extracted by dichloromethane and the solvent was distilled off under vacuum. The obtained product was dissolved in ethyl acetate and cooled to 0-5 °C and 100 mL of ethyl acetate hydrochloride was added slowly for a period of 30-60 min and stirred for 2-3h. The solid obtained was filtered and washed with precooled acetone. The obtained solid was dried to afford 2-(4-(3-(2-(trifluoromethyl)-l OH-phenothiazin-10-yl) propyl) piperazin-1-yl) ethanol dihydrochloride (1).
Yield: 62%, Purity: 99.2%.
EXAMPLE 4: Alternative process for Preparation of 2-(4-(3-(2-(trifluoro methyl)-10H-phenothiazin-10-yI) propyl) piperazin-1-yl) ethanol dihydro chloride (Fluphenazine dihydrochloride) (1)
To 100 g of 10-(3-chloropropyl)-2-(trifluoromethyl)-10H-phenothiazine (3), 51.67 g of potassium carbonate and 55 g of potassium iodide were added at 25-30 °C. To the reaction mixture 69 g of 2-(piperazin-l-yl) ethanol (2) was added and heated to 70-75 °C, stirred for 12-13 h. After completion of the reaction, the reaction mass was filtered. The filtrate was distilled under reduced pressure and degassed to afford crude 2-(4-(3-(2-(trifluoromethyl)-1 OH-phenothiazin-10-yl) propyl)piperazin-1 -yl)ethanol. To this, 400 mL of toluene and 400 mL of 50% hydrochloric acid were added and stirred. The organic and aqueous layers were separated. The pH of the

aqueous layer was adjusted to 7.5-8 by sodium carbonate solution. The product was extracted by dichloromethane and the solvent was distilled off under vacuum. The obtained product was dissolved in ethyl acetate and cooled to 0-5 °C and 100 rnL of ethyl acetate hydrochloride was added slowly for a period of 30-60 min and stirred for 2-3 h. The solid obtained was filtered and washed with precooled acetone. The obtained solid was dried to afford 2-(4-(3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl) propyl) piperazin-1-yl) ethanol dihydrochloride (1). Yield: 59%, Purity: 99%.
EXAMPLE 5 : Purification of Fluphenazine dihydrochloride (1)
100 g of Fluphenazine dihydrochloride (1) obtained in example 3 was dissolved in 400 mL of methanol at 25-30 °C. Then the reaction mass was heated to 60-65 °C and stirred for 30 min. The reaction mixture was cooled to 25-30 °C and stirred for
1 -2 h. The reaction mixture was filtered, and 6 volumes of methyl tertiary butyl
ether was added to the filtrate. The reaction mass was cooled to 20-25 °C,
maintained for 2 h and filtered under vacuum. The obtained solid was washed with
methyl tert-butyl ether and dried at 40-45 °C to result pure Fluphenazine
dihydrochloride (1). Yield: 83%, Purity: 99.9%. XRD: as shown in figure-1.
EXAMPLE 6: Purification of Fluphenazine dihydrochloride (1)
100 g of Fluphenazine dihydrochloride (1) obtained in example 3 was dissolved in 800 mL of ethanol at 25-30 °C. Then the reaction mass was heated to 60-65 °C and stirred for 30 min. The reaction mixture was cooled to 25-30 °C and stirred for 1-2 h. The reaction mixture was filtered, and 6 volumes of methyl tertiary butyl ether was added to the filtrate. The reaction mass was cooled to 20-25 °C, maintained for
2 h and filtered under vacuum. The obtained solid was washed with methyl tertiary
butyl ether and dried at 40-45 °C to result pure Fluphenazine dihydrochloride (1).
Yield: 83%, Purity: 99.9%
EXAMPLE 7: Preparation of N-phenyl-3-(trifluoromethyl)aniline (6)
To a mixture of 3-(trifluoromethyl)aniline (15) and bromobenzene (14), dimethyl formamide, toluene were added at 25-30 °C. The reaction mixture was cooled to 0-

5 °C and formic acid was added slowly and stirred for 2h to form N-phenyl-N-(3-(trifluoromethyl)phenyl) formamide (13). The reaction mixture was heated to 80-85 °C, copper carbonate and potassium carbonate were added, stirred for 2h. The reaction mass subjected to acid hydrolysis by using hydrochloric acid, and the layers were separated. The solvent was removed under high vacuum to afford N-phenyl-3-(trifluoromethyl)aniline (6).
EXAMPLE 8: Preparation of 2-(piperazin-l-yl) ethanol (2)
To 100 g of piperazine (16), 200 mL of water was added at 25-30 °C. The reaction mixture was cooled to 10-15 °C and 10 g of ethylene oxide was added and stirred for 30 min. The reaction mixture was heated to 30-35 °C and stirred for 2h. The product was separated by fractional distillation to afford 2-(piperazin-l-yl) ethanol (2).

We claim:
1. A process for the preparation of Fluphenazine dihydrochloride (1) having purity greater than 99.0% comprising:
a) reacting N-phenyl-3-(trifluoromethyl) aniline (6)

with sulphur and iodine to form 2-(trifluoromethyl)-10H-phenothiazine (5);

b) condensing 2-(trifluoromethyl)-10H-phenothiazine (5) with
chlorobromopropane (4)

in the presence of a base and a phase transfer catalyst to form 10-(3-chloropropyl)-2-(trifluoro methyl)-lOH-phenothiazine (3);

and
c) reacting 10-(3-chloropropyl)-2-(trifluoromethyl)-10H-phenothi
azine (3) with 2-(piperazin-l-yl) ethanol (2)

in the presence of a base, alkaline iodide and a phase transfer catalyst to form 2-(4-(3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl) propyl) piperazin-1-yl) ethanol dihydro chloride (1).
2. The process according to claim 1, wherein the base used in step b) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and lithium hydroxide.
3. The process according to claim 1, wherein the alkaline iodide used in step c) is selected from sodium iodide, potassium iodide.
4. The process according to claim 1, wherein the phase transfer catalyst used in step b), step c) is selected from tetra propylammonium bromide, tetra butylammonium bromide, tributyl benzylammonium bromide, tetraoctyl ammonium bromide, tetrabutyl ammoniumhydrogen sulfate, benzyltriethyl ammonium bromide, tetrabutylammonium acetate, tetrabutylammonium iodide.
5. A process for the purification of Fluphenazine dihydrochloride (1), which comprises of:
i. providing a solution of Fluphenazine dihydrochloride (1) in a
suitable protic solvent or a mixtures thereof; ii. heating the reaction mixture to a suitable temperature; iii. cooling the reaction mixture to a suitable temperature; iv. filtering the reaction mixture and adding suitable aprotic solvent;
and v. isolating pure Fluphenazine dihydrochloride (1).
6. The process according to claim 5, wherein the suitable protic solvent is selected from the group comprising of ethanol, methanol, isopropyl alcohol, water or mixtures thereof.
7. The process according to claim 5, wherein the aprotic solvent used is selected from the group comprising of ethyl acetate, tetrahydrofuran,

dichloromethane, toluene, acetonitrile, cyclohexane, diethyl ether, methyl tertiary butyl ether or the like.
8. A process for the preparation of N-phenyl-3-(trifluoromethyl) aniline (6)

by reacting 3-(trifluoromethyl) aniline (9)

with bromobenzene (8)

in presence of formic acid to form N-phenyl-N-[3-(trifluoromethyl) phenyl] formamide (7),

which was treated with copper carbonate and potassium carbonate and acid hydrolysedto formN-phenyl-3-(trifluoromethyl) aniline (6).
9. A process for the preparation of 2-(piperazin-l-yl) ethanol (2)

by reacting piperazine (11)

withoxirane (10)

to form a mixture of 2-(piperazin-l-yl) ethanol (2) and 2,2'-(piperazine-1,4-diyl)diethanol (If)

which on distillation yielded 2-(piperazin-l-yl) ethanol (2).