Field of the Invention
The present invention relates to a process for the preparation of Perphenazine. The
present invention also reIates to the processes for the purification of Perphenazine.
Background of the Invention
The substance Perphenazine and its non-toxic salts thereof is known fiom US2838507
by G.D. Searle and Co. Perphenazine is- known by brand name Trilafon. It is a typical
antipsychotic drug. Chemically, it is classified as a piperazinyl phenothiazine.
Perphenazine is used to treat psychosis (e.g. in people with schizophrenia and the
manic phases of bipolar disorder). Perphenazine effectively treats the positive
symptoms of schizophrenia, such as hallucinations and delusions, but its effectiveness
in treating the negative symptoms of schizophrenia, such as flattened affect and
poverty of speech, is unclear.. It is also marketed in combination with A.mitriptyline
hydrochloride and known as Etrafon:
Perphenazine is chemically known as 2-[4-[3-(2-chloro-1OH-phenothiazin-10-yl)
propyll-piperazin-1 -yl]-ethanol, which is represented by Formula 1.
Formula - I
US2838507 describes a process for the preparation of Perphenazine by reacting 2-
chloro-10-y-chloropropy1)-phenothiazine of Formula 5 with piperazine of Formula 2 . .
in the iiesence of sodium iodide and butanone at reflux to form 2-chloro-lO[y-(Npiperazino)
propyl]phenothiazine of Formula 3, which is further reacted with 2-bromoethanol
in the presence of potassium carbonate and toluene at reflux. The reaction
mixture obtained is treated with water, benzene and the organic layer is separated,
washed with water,' dried over anhydrous potassium carbonate,' filtered and
evaporated. The residue is distilled to yield Perphenazine of Formula 1. This is further
converted into its dihydrochloride salt.
. .
alnCNa'l; , * . alnC' HO-';
K2C03;Toluene
Formula 5 piperazine Formula - 3 Formula - I
Formula 2
This patcnt US'507 also gcncricnlly di3clo3cd mother method of preparation of
Perphenazine of Formula 1 and its non-toxic salts thereof, by condensing
haloalkylhalophenothiazine of Formula 2A with a piperazine of Formula 2B. . ,
n
And HNyN-R
~ l k - ~ a l o ~ e n
Formula 2A . . . Formula 2B
Wherein X is a halogen atom, Alk represents a bivalent saturated aliphatic
hydrocarbon radical derived fiom a straight or a branched chain hydrocarbon such as
ethylene, propylene, and butylene, like thereof. The radical R represents a
hydroxylated lower alkyl radical such as hydroxyethyl, hydroxypropyl,
dihydroxypropyl, hydroxybutyl and like thereof.
Another, patent US2860138 describes a process for the preparation of Perphenazine
of Formula 1 comprises to a suspension of sodamide in liq. ammonia added 2-chloro-
10H-phenothiazine of Formula 6 followed by addition of 1 -bromo-3-chloropropane of
Formula 6A to obtain ccimpound of 2-chloro-10'-(3-chloropropyl)-1 0H-phenothiazine
of Formula 5. The compound is isolated fiom the reaction mixture by evaporation of
ammonia, adding water, and extracting with ether to obtain oily compound. Further
heating a mixture of 1-(2-hydroxyethy1)-piperazine of Formula 4 and 2-chloro-10-(3-
chloropropy1)-lOH-phenothiazine of Formula 5. The reaction mixture is decomposed
by the addition of water and the aqueous mixture is extracted several times with ether.
1 The ether layer is then extracted with dilute hydrochloric acid. The acid layer is
basified with sodium hydroxide solution and.the resulting oil is extracted with ether.
The ether extracts are dried, concentrated and the residue distilled, yielding the oily
compound Perphenazine of Formula. 1 having a B. pt. of 278-281°C (1.0 rnrn). It is
further converted into its dihydrochloride salt in ethanolic hydrogen chloride melts at
225-226"C, after recrystallization from ethanol.
H N
Formula 6A Formula 4
Formula 6
Formula 5 Formula - 1
This patent US'i38 invoives use of ammonia and solvents like ether and its
evaporation, these are neither environment friendly nor suitable for use on industrial
scale.
None of patents described above disclosed yield and purity of obtained compound
Perphenazine of Formula 1.
Another Hungarian patent HU4519A2 disclosed a process for the preparation of
preparation of Perphenazine by heating 2-chloro-1 OH-phenothiazine of Formula 6 and
N-(3-chloropropy1)-N'-(2-hydroxyethy1)piperazine of Formula 7 in the presence of
xylene -H20 solvent mixture and NaOH.
Formula 6
CI
Formula 7
Formula - I
Japan patent application JP35007069 disclosed a process for the preparation of'
Perphenazine of Formula 1 by firstly dissolving 2-chloro- 10-,[3- bis(P-hydroxyethyl)
aminopropyl] phenothiazine in CHCb and treated with thionyl chloride to give 2-
chloro- 10-[3-bis(P-chloroethyl) aminopropyl]phenothiazine. Further reacted with
ethanolamine to get desired compound.
This process' is not suitable for industrial scale as thionyl chloride is corrosive in
nature and low temperature is required for this type of reactions.
Thus, there is a need to develop a simple, cost effective, high yielding and easy to
implement on industrial scale process for the preparation of Perphenazine of Formula
1.
Object of the hivention
One object of the present invention is to provide an improved, efficient, safe and
convenient process for preparation of Perphenazine.
Another object of the present invention is to provide a process for the purification of
Perphenazine by using acid base treatment method.
Further another object of the present invention is to provide a process for the
purification of Perphenazine by treatment with activated carbon.
Summarv of the invention
In accordance with principal embodiment, the present invention provides a process for
the preparation of Perphenazine of Formula 1, comprising the steps of:
(a) reacting of 2-chloro- 1 OH-phenothiazine of Formula 6
Formula 6
with 1-bromo-3-chloropropane of Formula 6A in presence of a suitable
solvent and a base
Formula 6A
to provide 2-chloro- 10-(3 -chloropropyl)- 1 OH-phcnothiazinc of Formula 5
Formula 5
optionally isolating the compound of Formula 5,
(b) reacting with 1-(2-hydroxyethy1)-pipcrazinc of Formula 4, optionally in the
presence of suitable solvent, base and an activating agent
Formula 4
to provide Perphenazine of Formula 1,
. .
(c) optionally purifying with acid base treatment;
(d) optionally treating with activated carbon and;
(e) isolating pure compound of Formula 1.
In accordance yith another embodiment, the present invention provides a process for
the purification of Perphen~ine of Formula 1 by acid-base treatment, which
comprises the steps of:
(a) contacting Perphenazine with a suitable solveni;
(b) optionally adding water;
(c) adjusting pH by using acid;
(d) separating 'aqueous layer;
(e) adding suitable solvent;
(f) adjusting pH by using suitable base and;
(g) 'isolating compound of Formula 1.
In accordance with yet another embodiment, the present invention provides a process
for the purification of Perphenazine of Formula 1 by treatment with activated carbon,
which comprises the steps of:
(a) contacting Perphenazine 'with a suitable solvent;
(b) optionally heating to dissolve the solid;
(c) adding activated carbon;
('d) fllrering the reaction mixture;
(e) cooling the reaction mixture to suitable temperature and;
(f) isolating compound .of Formula 1.
In accordance with yet another embodiment, the present invention provides a process
for the preparation of Perphenazine of Formula 1, which comprises the steps of:
(a) reacting of 2-chloro- 1 OH-phenothiazine of Formula 6
Formula 6
with 1-bromo-3-chloropropane of Formula 6A in presence of dimethyl
sulfoxide (DMSO) and sodium hydroxide
B ~ ~ C I
Formula 6A
Lo provide 2-chloro- 10-(3 -chloropropyl)- 1 OH-phenothiazine of Formula 5
Formula 5
(b) removing the solvent, reacting with 1-(2-hydroxyethy1')-piperazine of' Formula
4, in the presence of acetone, sodium carbonate and sodium iodide
to provide Perphenazine of Formula 1,
(c) dissolving reaction mixture of step (b) in mixture of toluene and water;
(d) acidifying the mixture of step (c);
(e) separating aqueous layer, adding toluene;
(f) basifying the mixture of step (e);
(g) optionally washing the reaction mixture with aq. solution of sodium
thiosulfate;
(h) concentrating the organic layer and dissolving the mass in acetone and;
(i) isolating compound of Formula 1.
In accordance with yet 'another embodiment, the present invention provides
Perphenazine which is substantially free of acrolein.
Detail description of the drawings:
Fig. 1. XRD of Perphenazine obtained according to example 2.
Fig.2. XRD of ~erphenazineo btained according to example 3.
<, ,
Detail description of the invention
The present invention provides an efficient and industrially advantageous process for
the preparation of Perphenazine of Formula 1.
Accordingly, the present invention also provides a process for the preparation of
Perphenazine of Formula 1' comprising the steps of reacting 2-chloro-1OHphenothiazine
of Formula 6 with 1-bromo-3-chloropropane of Formula 6A in the
presence of suitable solvent and base. Generally reaction may be carried out at a
temperature of 0 to 50°C for few minutes to few hours or till completion of reaction.
Preferably reaction is conducted at a temperature of 0 to 20°C, More preferably
reaction is conducted at a temperature of 0 to 10°C and it takes 2 to 5 hours for
c6mpletion of the reaction. The reaction completion is monitored by techniques such
as thin layer chromatography (TLC), high performance liquid chromatography
(HPLC), ultra performance liquid chromatography (UPLC) and like thereof.
Suitable solvent includes but not limited to organic solvents from the group
comprising of sulfoxide, amide, esters, ketone, nitrile, aliphatic or aromatic
hydrocarbons selected from such as dimethyl sulfoxide (DMSO), dimethylformamide
(DMF), ethyl acetate, propyl, acetate, butyl acetate, acetone, propanone, butanone,
methyl isobutyl ketone, acetonitrile, toluene, xylenes and the like or mixture thereof,
preferably solvent used is DMSO.
The base used may be selected from organic or inorganic base, wherein inorganic
base is selected from alkali or alkaline earth metal hydroxides, 'carbonates,
bicarbonates selected from such as sodium hydroxide, potassium hydroxide, calcium
hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium
carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium
bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate,
cesium bicarbonate, sodium with liquid ammonia, sodarnide or the like and mixture
thereof. Organic base is selected from methyl amine, ethyl arnine, diisopropyl ethyl
amine, triethyl mine, tributyl amine, N-methyl morpholine; preferably base used is
sodium hydroxide.
After completion of reaction, the 2-chloro- 10-(3-chloropropy1)- 1 OH-phenothiazine of
Formula 5 may be isolated or directly converted to ~er~henazinofe F ormula 1.There
may be formation of acrolein along with compound of Formula of 5, which may be
formed during the preparation of compound'of Formula 5. The acrolein formed can be
I removed at this stage only or at the final step of the preparation of Perphenazine by
I any suitable method known in the art such as washing the reaction mixture with
suitable solution or by dissolving in suitable solvent; specifically, washing the
reaction mixture with aq. solution of sodium thiosulfate. The compound 2-chloro-10-
(3-chloropropy1)- 1 OH-phenothiazine of Formula 5 is reacted with 1-(2-hydroxyethy1)-
piperazine of Formula 4 optionally in presence of suitable solvent and a base.
Activating agent such as sodium iodide (N~I)p, otassium iodide and like thereof may
also be added, preferably activating agent used is sodium iodide. .Generally reaction
may be carried out at a temperature of 15°C to reflux temperature for few minutes to
few hours or till completion of reaction. Preferably reaction is conducted at a
temperature of 15°C to reflux temperature, more preferably reaction is conducted at a
temperature of 40 to 60°C.
' Solvent used during reaction of 2-chloro- 10-(3-chloropropy1)- 1 OH-phenothiazine with
compound of Formula 5 may be selected from but not limited to organic solvents
selected from ketone such as acetone, propanone, butanone, methyl isobutyl ketone
and the like or mixture thereof; hydrocarbons are selected from aliphatic
hydrocarbons or aromatic hydrocarbons. Aliphatic hydrocarbons are selected from the
group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane,
octane, cyclohexane, cyclopentane and the like. Aromatic hydrocarbons are selected
from the group comprising of toluene,' xylene and the like thereof, preferably solvent
used is acetone. The base used may be selected from organic or inorganic base,
wherein inorganic base is selected from .alkali or alkaline earth metal hydroxides,
carbonates, bicarbonates selected from the group comprising of sodium hydroxide,
potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide,
sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate,
cesium carbonate, sodium bicarbonate,' potassium bicarbonate, calcium bicarbonate,
, magnesium bicarbonate, cesium bicarbonate or the like thereof, preferably base used
is sodium carbonate.
Accordingly, the present invention further also provides a process for the purification of
Perphenazine.of Formula 1 by acid base treatment comprising contacting Perphenazine
with organic solvent and optionally adding water. Further, acid is added to adjust the pH
below 3, preferably pH is below 1. The acid used may be selected from hydrochloric
acid, hydrobromic acid, sulphuric acid. Generally addition may be carried out at a
temperature of 0-40°C in few minutes to few hour, preferably addition is carried out at a
temperature of 20-40°C. The aqueous layer is separated and organic solvent is added,,
followed by addition of suitable base for adjusting pH between 10-14. The reaction
mixture is stirred and extracted using organic solvent, optionally washed with a solution
of sodium bisulfite followed by washing with sodium thiosulfate solution and water.
Evaporation of organic solvent, followed by dissolution in organic solvent heating,
cooling and isolating Perphenazine of Formula 1.
Organic solvent is selected from group comprising of nitriles, alcohols, ketones, esters,
halogenated hydrocarbons, ethers, arnides, hydrocarbons, and the like or mixture thereof.
Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile,
valeronitrile and the like. Alcohols are selected from the group comprising of methanol,
ethanol, n-propanol, isopropanol, n-butanol and the like. Ketones are selected from the
group comprising of acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone and
the like. Esters are selected from the group comprising of ethyl acetate, propyl acetate,
isopropyl acetate, butyl acetate and the like. Halogenated hydrocarbons are selected from
the group comprising of dichloromethane (DCM), chloroform, dichloroethane,
chlorobeqzene and the like. Ethers are selected from the group comprising of diethyl ether,
methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane and the
like. Amides are selected from the group comprising of N,N-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA), N-methylformamide, N-methylpyrrolidone and the like.
Aliphatic hydrocarbons are selected from the group comprising of alkanes or cycloalkanes
such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like.
Aromatic hydrocarbons are selected from the group comprising of toluene, xylene and the
like. Preferably, organic solvents used are toluene or acetone.
. .
Base used is inorganic base selected from the group comprising of alkali or alkaline earth
metal hydroxides, carbonates, bicarbonates selected from such as sodium hydroxide,
potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide,
sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, cesium
carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium
bicarbonate, cesium bicarbonate, preferably suitable'base used is sodium hydroxide.
The present invention further provides a process for the purification of ~erphenazine
of Formula 1 by treatment with activated carbon/silica gel comprising the steps of
contacting Perphenazine with a suitable solvent followed by treating with activated
carbon, optionally silica gel treatment may also be prolided. The activated carbon
treatment can be performed at a temperature of 25°C to reflux temperature of solvent
for 30 to 60 minutes, Preferably activated carbon may be done at 40 to 65OC, more
preferably carbon treatment is done at 50 to 60°C. The carbon or silica gel can be
removed by the suitable technique such as centrifugation, direct filtration ,or filtration
through hyflo. Suitable solvent may be selected from group comprising of nitriles,
alcohols, ketones, esters, halogenated hydrocarbons, ethers, amides, hydrocarbons,
and the like or mixture thereof. preferably the solvent selected is acetone. Thereafter
cooling the reaction mixture at -10 to 25OC, preferably -5 to 5OC to precipitate the
desired compound. The resulting compound Perphenazine of ~ormul'a 1 can be
isolated by suitable techniques such as filtration, centrifugation and the like thereof
known in the art.
Major advantages realized in the present invention are that process can be easily and
. .
conveniently scaled-up for industrial large scale production. The process is simple
economic with high throughput, operationally efficient and environment friendly.
Although the following examples illustrate the present invention in more detail but the
examples are not intended in any way to limit the scope of the present invention. It
will thus be readily apparent to the one skilled in the art that varying substitutions and
modifications may be made to the invention disclosed herein without departing from
the scope and spirit of the invention. Thus it should be understood that although the
present invention has been specifically disclosed by preferred embodiments and
optional features. modifications and variation of the concepts herein disclosed may be
resorted to by those skilled in the art and that such modifications and variations are
considered to be falling within the scope of the invention.
Example 1
! Preparation of 2-chloro-10-(3-chloropropy1)-10H-phenothiazine:
To the mixture of 2-chloro- 1 OH-phenothiazine (1 50gm) in dimethyl ~ulfoxide
(600ml) was added a solution of sodium hydroxide (64gm in 67ml in water), stirred
and cooled the reaction mixture to 0-10°C. To this mixture was added a solution of 1-
bromo-3-chloro propane in dimethyl sulfoxide (202.5gm in 150ml). Stirred the
reaction mixture for 2-3 h at 0-10°C. After completion of reaction, toluene was added
1 followed by addition of water. Stirred and separated the layers. The organic layer was
I
again extracted with toluene. Separated the layers and combined both the organic
layers. Distilled under vacuum to obtain 200.0gm of title compound.
Example 2
Preparation of Perphenazine:
To the mixture of 2-chloro- 10-(3-chloropropy1)- 1 OH-phenothiazine (200gm) in
acetone (450ml) was added powdered sodium carbonate (8 1.7gm), 1 -(2-hydroxyethyl)
piperazine (183.8gm) and sodium iodide (19.2 gm). The reaction mixture was
refluxed for 12-1 5 h. After completion of reaction, water (450ml) and toluene (450ml)
of was added, stirred and separated the layers. To the organic layer was added water
(450ml) and acidified with hydrochloric acid to pH below 1.0. Separated the layers
followed by addition of toluene (450ml) to the aqueous layer and basified by using
sodium hydroxide to pH above 12.0. Separated the layers, washed the organic layer
with a solution of aq. .sodium bisulfate followed by washing with aq. solution of
sodium thiosulfate and then with water. Concentrated the organic layer added acetone
(450ml), dissolved and cooled. Filtered, washed with a mixture of acetone: n-hexane
and dried under vacuum to obtain the 158.0gm of title compound.
Example 3
Purification of Perphenazine:
The mixture of Perphenazine (125gm) in acetone (375m1) was stirred a reflux
temperature 50-60°C. To it, activated carbon (6.25gm) was added. The reaction
mixture was stirred for 30-60 min at 55-60°C, filtered the reaction mixture. Cooled to
room temperature, stirred.for 2-3 hours. The reaction mixture was further cooled to -5
to 50C. Filtered, washed with acetone and dried under vacuum to obtain 100.0 gm of
the pure compound.
Example 4
Preparation of 2-chloro-10-(3-chloropropyl)-10H-phenothiazine:
To the mixture of 2-chloro-lOH-phenothiazine (1 50gm) in dimethyl sulfoxide
(600ml) was added a solution of sodium hydroxide (64gm in 67ml in water), stirred
and cooled the reaction mixture to 0-10°C. To this mixture was added a solution of 1-
bromo-3-chloro propane in dimethyl sulfoxide ( 2 0 2 . 5 ~in 150ml). Stirred the
reaction mixture for 2-3 h at 0-lo0 C. After completion of reaction, toluene was added
followed by addition of water. Stirred and separated the layers. The organic layer was
again extracted with toluene. Separated the layers and combined both the organic
layers. Distilled, added n-pentane (600ml), stirred for 10- 12 hours, filtered, and
washed with n-pentane. Dried under vacuum to obtain the title compound.
Example 5
Preparation of Perphenazine
To the mixture of 2-chloro-lOH-phenothiazine (150gm) in dimethyl sulfoxide
(600ml) was added a solution of sodium hydroxide (64gm in 67ml in water), stirred
and cooled the reaction mixture to 0-10°C. To this mixture was added a solution of lbromo-
3-chloro propane in dimethyl sulfoxide (202.5gm in 150ml). Stirred the
reaction mixture for 2-3 h at 0-10°C. After completion of reaction, toluene was added
followed by addition of water. Stirred and separated the layers. The aqueous layer was
again extracted with toluene. Combined both the organic layers and concentrated the
reaction mixture. To the said mixture in acetone (450ml) was added powdered sodium
carbonate (8 1.7gm), 1 -(2-hydroxyethy1)piperazine (1 83.8gm) and sodium iodide
(19.2gm). The reaction mixture was refluxed for 12-15 h. After completion of
reaction, water (450ml) and toluene (450ml) was added, stirred and separated the
layers. To the organic layer was added water (450ml) and acidified with hydrochloric
acid to pH below 1 .O. Separated the 'layers followed by addition of toluene (450ml) to
the aqueous layer and basified by using sodium hydroxide to .PI-I above 12.0.
Separated the layers, washed the organic layer with a solution of aq. sodium bisulfate
followed by washing with aq. solution of sodium thiosulfate and water. Concentrated
the organic layer, added acetone (450ml) further heatcd and cooled. Filtered, washed
with a mixture of acetone: n-hexane and dried under vacuum to obtain the 158,.0gm of
title compound.

We Claim:
1. A process for the preparation of Perphenazine of Formula 1 comprising the
steps of:
(a) reacting of 2-chloro- 1 OH-phenothiazine of Formula 6.
with 1-bromo-3-chloropropane of Formula 6A in presence of a. suitable
solvent and a base
~r-cl
Formula 6A
to provide 2-chloro- 10-(3 -chloropropyl)- 1 OH-phenothiazine of Formula 5
Formula 5
optionally isolating the compound of Formula 5;
(b) reacting compound of Formula 5 with 1-(2-hydroxyethy1)-piperazine of
'Formula 4, optionally in the presence of suitable solvent, base and an
activating agent
n
HN~N\,,
Formula 4
to provide Perphenazine of Formula 1 ;
(c) optionally purified using acid base treatment;
- ~ ~ ~ ~ Q , ~ ~ - h , H ~ -12,Qf-E Zi--a.-J. ,5 E 7 : 3G- - -- - - -- --- -
, 16
-- - --
(d) optionally treated with activated carbon and;
(e) isolating the pure compound of Formula 1.
2. The process according to claim 1, wherein suitable solvent is selected from the
group comprising of sulfoxide, amide, esters, ketone, nitrile, aliphatic or
aromatic hydrocarbons such as dimethyl sulfoxide (UMSU),
dimethylformamide (DMF), ethyl acetate, propyl acetate, butyl acetate,
acetone, propanone, butanone, methyl isobutyl ketone, acetonitrile, toluene,
xylcnc OP mixturc thcrcof.
3. The process according 'to claim 1, wherein base used in steps (a) and (b) is
selected from alkali or alkaline earth metal hydroxides, carbonates,
bicarbonates; and activating agent used in step (b) is. selected from sodium
iodide (NaI) and potassium iodide.
4. A process for the purification of Perphenazine of Formula 1 comprising the
steps .of
(a) contacting Perphenazine with.a suitable solvent;
(b) optionally adding water;
(c) adjusting pH by using acid;
(d) separating aqueous layer;
(e) adding suitable solvent;
(f) adjusting pH by using suitable base and
(g) isolating compound of Formula 1.
5. The process according to claim 4, wherein solvents used in steps (a) and (e) is
selected from the group comprising of hydrocarbons, nitriles, alcohols,
ketones, esters, halogenated hydrocarbons, ethers, amides and mixtures
thereof.
6. The process according to claim 4, wherein acid used in steps (c) and (f) is
selected from group comprising of hydrochloric acid, hydrobromic acid,
sulfuric acid and basc is selected from alkali or alkaline earth metal
hydroxides, carbonates or bicarbonates. .
7. A process for the purification of Perphenazine of Formula 1, comprising the
steps of:
(a) contacting Perphenazine with a suitable solvent;
(b) optionally heating to dissolve the solid;
(c) adding activated carbon;
(d) filtering the reaction mixture;
(e) cooling the reaction mixture at suitable temperature and
(f) isolating compound of Formula 1.
8. The process according to claim 7, wherein solvent used in step (a) is selected
fiom the group comprising of nitriles, alcohols, ketones, esters, halogenated
hydrocarbons, ethers, amides, hydrocarbons, and the like or mixture thereof.
9. A process for the preparation of Perphenazine of Formula 1, which comprises
the steps of:
(a) reacting of 2-chloro- 1 OH-phenothiazine of Formula 6
Formula 6
with 1-bromo-3-chloropropane of Formula 6A. in presence of dimethyl
sulfoxide and sodium hydroxide
Formula 6A
to provide 2-chloro- 1 0-(3 -chloropropyl)- 1 OH-phenothiazine of Formula 5
(b) reacting compound of formula 5 with 1-(2-hydroxyethy1)-piperazine of
Formula 4, in the presence of acetone, sodium carbonate and sodium iodide
Formula 4
to provide Perphenazine of Formula 1
(c) dissolving reaction mixture of step (b) in mixture of toluene and water;
(d) aciditjrlng the mixture of step (c);
(e) separating aqueous layer, adding toluene;
(f) basifying the mixture of step (e);
(g) optionally washing the reaction mixture with aq. solution of sodium
thiosulfate;
(h) concentrating the organic layer and dissolving the mass in acetone and
(i) isolating compound of Formula 1
10. Perphenazine, substantially free of acrolein.