The present invention relates to a process for the preparation of 8-chloro-ll-(4-methyl-l-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine of Formula I or pharmaceutically acceptable salts, and process of purification thereof.
\ N

NH
CI
Formula I
The present invention further provides solid forms of 8-chloro-ll-(4-methyl-l-
piperazinyl)-5h-dibenzo [b,e] [1,4] diazepine of Formula I or pharmaceutically
acceptable salts, and process of preparation thereof.
BACKGROUND OF THE INVENTION
Clozapine chemically known as 8-chloro-ll-(4-methyl-l-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine, represented by Formula I, is sold under the trade name Clozaril. Clozapine is an atypical antipsychotic medication, which is used to treat certain mental/mood disorders (schizophrenia, schizoaffective disorders) by helping to restore the balance of certain natural substances (neurotransmitters) in the brain.
N
N* \=

NH
u
CI
Formula I
U.S. 3,539,573 describes a process for the preparation of clozapine using 2-amino-4-
chlorodiphenylamine-2'-carboxylic acid (4"-methyl)piperazide and POCb in the presence
of N,N-dimethylaniline.

U. S. 3,962,248 describes a process for the preparation of clozapine wherein a solution of toluene, anisole of titanium tetrachloride is added to a mixture of N-methyl piperazine and toluene followed by the addition of 8-chloro-10,11 -dihydro-11 -oxo-5H-dibenzo[b,e][l,4]-diazepine and N-methyl piperazine, and heated to boil (110°-112°) to obtain clozapine which was further crystallized to obtain pure clozapine.
SU 920055 discloses the process for preparation of clozapine by intramolecular cyclization of 4-methylpiperazide N-(2-amino-4-chlorophenyl)-anthranilic acid under the influence of diethirates of tetrachloride.
WO 2019/239202 Al discloses a process for the preparation of clozapine as shown in the Scheme-1 and Scheme-2 below:
Scheme-1:

^--^
CI\^r\.N02 halo benzene QI
NH2 DMF

NO, Cl
acetyl chloride
SJ
NH

NO-
A,

sodium dithionate

vo
N
NH
CI

NH
A-

N H

— CI

T P0CI3
NH
Ar

CI

Clozapine

Scheme-2:



Sodium dithinate

ethylchloroformate

vo
^
N
NH
HN H

N H

CI

The processes as described in prior published references, result with a product having many impurities, which impacts the overall yield. Also, the work up processes as disclosed in the prior references are more cumbersome, tedious and time consuming. To avoid the above stated drawbacks, present invention provides a simple and cost effective process for preparation of clozapine wherein, the workup and isolation of product is simple as compared to the processes disclosed in prior published references.
OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved, cost effective and environment friendly process for the preparation of clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof.
Another object of the present invention is to develop a purification process to obtain substantially pure clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof which is reproducible at large scale production.
SUMMARY OF THE INVENTION
The main aspect of present invention is to provide a process for the preparation of 8-chloro-ll-(4-methyl-l-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine (clozapine) of Formula I or pharmaceutically acceptable salts, hydrates thereof,
b
Formula I
wherein said process comprising the steps of:
a) treating 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one with N-methylpiperazine, in the presence of a suitable solvent and catalyst to get clozapine;
b) optionally, purifying the clozapine in suitable solvent; and
c) optionally, converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.

The other aspect of present invention is to provide a process for the preparation of clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof,
\ N

NH
CI
Formula I
wherein said process comprising the steps of:
a) treating 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one with N-methylpiperazine and catalyst in the presence of anisole and suitable solvent to get clozapine;
b) optionally, purifying the clozapine in suitable solvent; and
c) optionally, converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.
The other aspect of present invention is to provide a process for the preparation of
clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof,
\ N

NH
CI
Formula I
wherein said process comprising the steps of:
a) treating 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one with N-methylpiperazine and catalyst in the absence of anisole and suitable solvent to get clozapine;
b) optionally, purifying the clozapine in suitable solvent; and
c) optionally, converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.

The other aspect of the present invention is to provide a process for the preparation of clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof,
\ N

NH
CI
Formula I
wherein said process comprising the steps of:
a) dissolving titanium tetrachloride in a suitable solvent to get a solution;
b) dissolving 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one in suitable solvent, optionally in presence of anisole to get a solution;
c) simultaneously adding N-methypiperazine and solution of step a) to the solution of step b);
d) heating the reaction mixture;
e) isolating to get clozapine; and
f) optionally, purifying the clozapine in suitable solvent; and
g) optionally, converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.
The other aspect of the present invention is to provide a process for the purification of clozapine or pharmaceutically acceptable salts, hydrates thereof, wherein said process comprising the steps of:
a) dissolving clozapine in one or more suitable solvent; and
b) isolating pure clozapine or pharmaceutically acceptable salts, hydrates thereof.
The other aspect of the present invention is to provide a process for the purification of clozapine or pharmaceutically acceptable salts, hydrates thereof, wherein said process comprising the steps of:
a) dissolving clozapine in a mixture of hydrocarbon and alcohol; and
b) isolating pure clozapine or pharmaceutically acceptable salts, hydrates thereof.

The other aspect of the present invention is to provide a process for preparing crystalline clozapine or pharmaceutically acceptable salts, hydrates thereof, wherein said process comprising the steps of:
a) dissolving clozapine in a suitable solvent; and
b) optionally adding anti-solvent; and
c) isolating crystalline clozapine or pharmaceutically acceptable salts, hydrates thereof.
The other aspect of the present invention is to provide a process for preparing crystalline clozapine or pharmaceutically acceptable salts, hydrates thereof, wherein said process comprising the steps of:
a) dissolving clozapine in an alcoholic solvent; and
b) optionally adding anti-solvent; and
c) isolating crystalline clozapine or pharmaceutically acceptable salts, hydrates thereof.
In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of clozapine or pharmaceutically acceptable salts, hydrates thereof, comprising the steps of:
a) providing a solution of clozapine or pharmaceutically acceptable salts, hydrates thereof in a suitable solvent;
b) adding a solution of atleast one pharmaceutically acceptable carrier in a suitable solvent to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of clozapine or pharmaceutically acceptable salts, hydrates thereof.
In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of clozapine or pharmaceutically acceptable salts, hydrates thereof, comprising the steps of:
a) providing a solution of clozapine or pharmaceutically acceptable salts, hydrates thereof in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier to the solution obtained in step a); and

c) isolating to get amorphous solid dispersion of clozapine or pharmaceutically acceptable salts, hydrates thereof.
DETAILED DESCRIPTION
DETAILED DESCRIPTION
Brief Description of the accompanying drawing
Fig. 1 represents the X-ray (powder) diffraction (XRPD) partem of the crystalline form
of Clozapine of Formula I.
Definitions:
"Suitable solvent or solvent" as used in the context of the present invention refers to polar or non-polar solvents selected from, but not limited to, alcohol such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated solvent such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxy ethanol, 2-ethoxyethanol, anisole; ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene, cyclohexane and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; water; and mixtures thereof.
"Catalyst" as used in the context of the present invention refers titanium, zirconium and hafnium, comprised in group IVb of the periodic system.

The terms "pharmaceutically acceptable salt" as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, hexanoic acid, hippuric acid, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, methane sulfonic acid, naphthalene sulfonic acid, 1 -hydroxy -naphthalene-2-carboxylic acid, palmitic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, galactaric acid, gentisic acid, ethane-1,2-disulfonic acid, trans-cinnamic acid, saccharin, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, stearic acid, vanillic acid, vanillin, benzenesulfonic acid, naphthalene-2-sulfonic acid, 4-aminosalicylic acid p-toluenesulfonic acid and the like. The inorganic salts may further includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like.
In one embodiment, the present invention provides a process for the preparation of 8-chloro-ll-(4-methyl-l-piperazinyl)-5h-dibenzo [b,e] [1,4] diazepine (clozapine) of Formula I or pharmaceutically acceptable salts, hydrates thereof,
N
N* \=

NH
11
CI
Formula I
wherein said process comprising the steps of:
a) treating 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one with N-methylpiperazine, in the presence of a suitable solvent and catalyst to get clozapine;
b) optionally, purifying the clozapine in suitable solvent; and

c) optionally, converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.
In another embodiment, the present invention provides a process for the preparation of clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof,
\ N

NH
CI'
Formula I
wherein said process comprising the steps of:
a) treating 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one with N-methylpiperazine and catalyst in the presence of anisole and suitable solvent to get clozapine;
b) optionally, purifying the clozapine in suitable solvent; and
c) optionally, converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.
In one another embodiment, the present invention provides a process for the preparation of clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof,
\ N
N // w

CANH
Formula I
wherein said process comprising the steps of:
a) treating 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one with N-methylpiperazine and catalyst in the absence of anisole and suitable solvent to get clozapine;
b) optionally, purifying the clozapine in suitable solvent; and

c) optionally, converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.
In another embodiment, the catalyst used in the step a) can be used in the form of solution in a suitable solvent or can be used as such.
In another embodiment, the present invention provides a process for the preparation of clozapine or pharmaceutically acceptable salts, hydrates thereof,
\ N



NH
CI
Formula I
wherein said process comprising the steps of:
a) dissolving titanium tetrachloride in a suitable solvent to get a solution;
b) dissolving 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one in suitable solvent in presence of anisole to get a solution;
c) simultaneously adding N-methypiperazine and solution of step a) in the solution of step b);
d) heating the reaction mixture;
e) isolating to get clozapine of Formula I;
f) optionally, purifying the clozapine in suitable solvent; and
g) optionally, converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.
In another embodiment, the present invention provides an improved process for the preparation of clozapine or pharmaceutically acceptable salts, hydrates thereof,

N



N n NX/ W
NH
CI
Formula I
wherein said process comprising the steps of:
a) dissolving titanium tetrachloride in a suitable solvent to get a solution;
b) dissolving 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one in suitable solvent in absence of anisole to get a solution;
c) simultaneously adding N-methypiperazine and solution of step a) in the solution of step b);
d) heating the reaction mixture;
e) isolating to get clozapine of Formula I;
f) optionally, purifying the clozapine in suitable solvent; and
g) optionally, converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.
In another embodiment, the catalyst used in the step a) can be used in the form of solution in a suitable solvent or can be used as such.
In another embodiment, the present invention provides a process for the preparation of clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof,
N
N* \=

NH
I;J
CI
Formula I
wherein said process comprising the steps of: a) dissolving titanium tetrachloride in a suitable solvent to get a solution;

b) dissolving 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one in suitable solvent, optionally in presence of anisole to get a solution;
c) adding N-methypiperazine and solution of step a) to the solution of step b);
d) heating the reaction mixture;
e) optionally, purifying the clozapine in suitable solvent; and
f) optionally, converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.
In another embodiment, the present invention provides a process for preparation of clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof, wherein the ratio of anisole to suitable solvent is 1: 100 to 1: 10 (v/v), preferably in the ratio of 1:100 to 1:20 (v/v).
In another embodiment, the present invention provides a process for preparation of clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof, wherein the molar ratio of anisole to suitable solvent is 0: 1 to 0.2: 1.
In preferred embodiment the present invention provides a process for preparation of clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof, wherein the molar ratio of anisole to toluene is 0.2:1, preferably between 0.015:1 to 0.025:1.
In another embodiment, the present invention provide a process for the purification of clozapine or pharmaceutically acceptable salts, hydrates thereof, wherein said process comprising the steps of:
a) dissolving clozapine in one or more suitable solvent; and
b) isolating pure clozapine or pharmaceutically acceptable salts, hydrates thereof.
In another embodiment, the present invention provide a process for the purification of clozapine or pharmaceutically acceptable salts, hydrates thereof, wherein said process comprising the steps of:
a) dissolving clozapine in a mixture of hydrocarbon and alcohol; and
b) isolating pure clozapine or pharmaceutically acceptable salts, hydrates thereof.

In specific embodiment, the hydrocarbon(s) used for purification of clozapine or pharmaceutically acceptable salts, hydrates thereof is selected from toluene, methanol, ethylacetate, acetone, acetonitrile and mixture thereof.
In another embodiment, the present invention provides a process for the purification of clozapine or pharmaceutically acceptable salts, hydrates thereof, wherein said process comprising the steps of:
a) treating crude clozapine with hot toluene and filtered to get filtrate;
b) adding water to the filtrate followed by separating the layers;
c) heating at 80-85°C to get a solution and then filtered;
d) washing the undesired solid with hot toluene at 80-85°C and collecting toluene layer;
e) distilling toluene to get solid mass;
f) adding methanol and toluene to the solid mass and heating at 60-65°C;
g) filtering and washing the undesired mass with methanol; h) distilling methanol partially;
i) cooling the mass at room temperature followed by cooling upto 0°C; and j) isolating the pure clozapine.
In another embodiment, the present invention provide a process for preparing crystalline clozapine or pharmaceutically acceptable salts, hydrates thereof, wherein said process comprising the steps of:
a) dissolving clozapine in a suitable solvent; and
b) optionally adding anti-solvent; and
c) isolating crystalline clozapine or pharmaceutically acceptable salts, hydrates thereof.
In a preferred embodiment, the present invention provide a process for preparing crystalline clozapine or pharmaceutically acceptable salts, hydrates thereof, wherein said process comprising the steps of:
a) dissolving clozapine in an alcoholic solvent; and
b) optionally adding anti-solvent; and
c) isolating crystalline clozapine or pharmaceutically acceptable salts, hydrates thereof.

In specific embodiment, the alcohol(s) used for purification of clozapine of Formula I is selected from methanol, ethanol, isopropanol, t-butanol, n-butanol and mixture thereof.
In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of clozapine I or pharmaceutically acceptable salts, hydrates thereof, comprising the steps of:
a) providing a solution of clozapine I or pharmaceutically acceptable salts, hydrates thereof in a suitable solvent;
b) adding a solution of atleast one pharmaceutically acceptable carrier in a suitable solvent to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of clozapine I or pharmaceutically
acceptable salts, hydrates thereof.
In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of clozapine I or pharmaceutically acceptable salts, hydrates thereof, comprising the steps of:
a) providing a solution of clozapine I or pharmaceutically acceptable salts, hydrates thereof in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of clozapine I or pharmaceutically acceptable salts, hydrates thereof.
In a preferred embodiment, the clozapine or pharmaceutically acceptable salts, hydrates thereof may be isolated by techniques such as purification, centrifugation, crystallization, filtration, extraction or evaporation, freeze drying, spray drying, lyophilization and other conventional techniques.
In one another preferred embodiment, clozapine or pharmaceutically acceptable salts, hydrates thereof obtained as per the process of the present invention is crystalline in nature. The clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof as obtained herein is substantially crystalline in nature with less than about 10% w/w of

amorphous form, preferably less than 5%w/w of amorphous form and most preferably less than 1% w/w of amorphous form.
In another embodiment, the present invention provides a crystalline clozapine, characterized by XRD partem having peaks (29 values) at 10.45, 13.05, 13.41, 13.93, 15.54, 16.30, 17.27, 18.47, 19.24, 19.64, 20.71, 20.91, 21.28, 21.62, 22.94, 23.63, 25.53, 26.18, 26.37, 26.84, 27.84, 27.84, 28.18, 28.62, 29.83, 30.07, 30.29, 30.83, 31.13, 31.66, 32.38, 33.03, 33.78, 34.28, 35.33, 35.61, 36.33, 37.46, 38.79, 39.10 and 39.36±0.2 as depicted in Fig-1.
In another embodiment, the present invention provides stable amorphous form of clozapine or pharmaceutically acceptable salts, hydrates thereof, wherein said clozapine or pharmaceutically acceptable salts, hydrates thereof is having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
In one another embodiment, clozapine or pharmaceutically acceptable salts, hydrates thereof obtained herein is amorphous in nature. The amorphous clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof obtained as per the process of the present invention is substantially free from crystallinity.
In an embodiment, the present application provides a stable solid dispersion of clozapine or pharmaceutically acceptable salts, hydrates thereof, with less than 5% of crystallinity, preferably with less than 1% crystallinity and more preferably with less than 0.5% crystallinity.
In another embodiment, the present invention provides clozapine or pharmaceutically acceptable salts, hydrates thereof, wherein clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof is crystalline or amorphous in nature or may be the mixture of amorphous and crystalline form.
In furthermore embodiment, there is provided a substantially pure clozapine of Formula I or salts, hydrates, wherein said clozapine of Formula I or salts, hydrates is substantially

about 0.1% w/w for impurity A and 0.3% for impurity B, C, and D or total impurity is less than about 1% w/w, more specifically less than about 0.15% w/w of any impurity;


NH
NH
CK /^ xN*(
H x=/
CI
O
Formula A , Formula B ■ Formula C

^) ^
A
N—/
H X^/
Formula B

Formula D , and N-Oxide impurity
In further embodiment, the present invention provides clozapine or pharmaceutically acceptable salts, hydrates thereof are characterized by particle size distribution of less than about 300um, preferably less than about 200um and most preferably about lOOum.
In one another embodiment, the clozapine or pharmaceutically acceptable salts, hydrates thereof prepared as per the process of the present invention, wherein said clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof is characterized by purity of 99.0% and above.
In one another embodiment, the present invention further provides a composition comprising clozapine or pharmaceutically acceptable salts, hydrates thereof as prepared by the process of the present invention along with one or more pharmaceutical acceptable excipients.
In another embodiment, the present invention provides a process for the preparation of an amorphous form of clozapine or pharmaceutically acceptable salts, hydrates thereof, comprising the steps of: a) providing a solution clozapine of Formula I or salts, hydrates thereof in a solvent;

b) lyophilizing the solution obtained in step a); and
c) isolating the amorphous form of comprising clozapine or pharmaceutically acceptable salts, hydrates thereof.
In another aspect, the present invention provides a process for the preparation of a premix of clozapine or pharmaceutically acceptable salts, hydrates thereof, comprising the steps of:
a) adding clozapine or pharmaceutically acceptable salts, hydrates thereof to at least one pharmaceutically acceptable carrier to get a solid mass;
b) optionally adding solvent to get a solution; and
c) isolating the premix of clozapine or pharmaceutically acceptable salts, hydrates thereof either by removal of solvent from solution of step b) or by isolating the solid mass of step a).
The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
EXAMPLES;
Example-1; Synthesis of 8-chloro-ll-(4-methylpiperazin-l-vl)-5H-dibenzo[b,el [l,41-diazepin-6-amine of Formula I
Charged 8-chloro-5,10-dihydro-dibenzo[b,e][l,4] diazepine-11-one (10 g), toluene (150 ml) and anisole (5 ml) in RBF. Reaction mixture was cooled to 5-15°C. Slowly added solution of titanium tetrachloride (9.7 ml in 20 ml Toluene) and N-methyl piperazine (20.14 g) dropwise simultaneously at the temperature of 0-20 °C. The reaction mass was stirred for 30 mins. The temperature of the reaction mass was raised to 110°C and stirred for 10 hours at 110-115°C. After completion, the reaction mixture was cooled to 80-85°C followed by the addition of NaOH (20g) and reaction mixture was further stirred at 80-85°C. Reaction mixture was filtered at 80-85°C to remove inorganic salt. The wet cake was washed with hot toluene (100ml). The filtrate was collected and washed with DM

(0.5g) and reaction mixture was stirred for 1 hour at 80-85°C. Reaction mixture was filtered from hyflo bed and washed with hot toluene (10 ml) at 80-85 °C. Toluene was distilled out under vacuum and degassed. Methanol (100 ml) and toluene (10 ml) were charged at 25-30°C. The reaction mixture was heated up to 60-65°C and stirred till the clear solution was obtained. The solution was filtered and washed with methanol (10ml) at 60-65°C. The filtrate was charged in RBF and distilled the methanol till half of the volume. The reaction mass was slowly cooled down to 20-25°C and further cooled to 0°C. The reaction mixture was stirred for 2 hours at 0-5°C and filtered. The wet cake was washed methanol (10 ml) and dried to get Clozapine (9 g) as light yellow powder. Results:
HPLC Purity (%) = > 99.5% Yield (%) = 71%
Example-2; Synthesis of 8-chloro-ll-(4-methylpiperazin-l-vl)-5H-dibenzo[b,el [l,41-diazepin-6-amine of Formula I
Charged 8-chloro-5,10-dihydro-dibenzo[b,e][l,4] diazepine-11-one (10 g), toluene (150 ml) in RBF. Added anisole (5 ml) and reaction mixture was cooled to 5-15°C. Added the solution of titanium tetrachloride (9.7 ml in 20 ml toluene) followed by N-methyl piperazine (20.14 g) dropwise at the temperature of 0-20°C. The reaction mass was stirred for 30 mins. The temperature of the reaction mass was raised to 110°C and stirred for 10 hours at 110-115°C. After the completion the reaction mixture was cooled to 80-85°C followed by the addition of NaOH (20g) and reaction mixture was further stirred at 80-85°C. Reaction mixture was filtered at 80-85°C to remove inorganic salt. The wet cake was washed with hot toluene (100ml). The filtrate was collected and washed with DM water (100 ml x 2). The organic layer was separated and charged in RBF. Added charcoal (0.5g) and reaction mixture was stirred for 1 hour at 80-85°C. Reaction mixture was filtered from hyflo bed and washed with hot toluene (10 ml) at 80-85 °C. Toluene was distilled out under vacuum and degassed. Methanol (100 ml) and toluene (10 ml) were charged at 25-30°C. The reaction mixture was heated up to 60-65°C and stirred till the clear solution was obtained. The solution was filtered and washed with methanol (10ml) at 60-65°C. The filtrate was charged in RBF and distilled the methanol till half of the volume. The reaction mass was slowly cooled down to 20-25°C and further cooled to 0°C.

The reaction mixture was stirred for 2 hours at 0-5°C and filtered. The wet cake was washed methanol (10 ml) and dried to get Clozapine (9 g) as light yellow powder.
Example-3; Synthesis of 8-chloro-ll-(4-methylpiperazin-l-vl)-5H-dibenzo[b,el [l,41-diazepin-6-amine of Formula I
Charged 8-chloro-5,10-dihydro-dibenzo[b,e][l,4] diazepine-11-one (10 g) and toluene (150 ml). Reaction mixture was cooled to 5-15°C. Slowly added solution of Titanium tetrachloride (9.7 ml in 20 ml toluene) and N-methyl piperazine (20.14 g) dropwise at the temperature of 0-20 °C. The reaction mass was stirred for 30 mins. The temperature of the reaction mass was raised to 110°C and stirred for 10 Hours at 110-115°C. After the completion the reaction mixture was cooled to 80-85 °C followed by the addition of NaOH (20g) and reaction mixture was further stirred at 80-85°C. Reaction mixture was filtered at 80-85°C to remove inorganic salt. The wet cake was washed with hot toluene (100ml). The filtrate was collected and washed with DM water (100 ml x 2). The organic layer was separated and charged in RBF. Added charcoal (0.5g) and reaction mixture was stirred for 1 hour at 80-85°C. Reaction mixture was filtered from hyflo bed and washed with hot toluene (10 ml) at 80-85°C. Toluene was distilled out under vacuum and degassed. Methanol (100 ml) and toluene (10 ml) were charged at 25-30°C. The reaction mixture was heated up to 60-65°C and stirred till the clear solution was obtained. The solution was filtered and washed with methanol (10ml) at 60-65 °C. The filtrate was charged in RBF and distilled the methanol till half of the volume. The reaction mass was slowly cooled down to 20-25°C and further cooled to 0°C. The reaction mixture was stirred for 2 hours at 0-5°C and filtered. The wet cake was washed methanol (10 ml) and dried to get Clozapine (9 g) as light yellow powder. Results:
HPLC Purity (%) = > 99.5% Yield (%) = 71%
Example-4; Synthesis of 8-chloro-ll-(4-methylpiperazin-l-vl)-5H-dibenzo[b,el [l,41-diazepin-6-amine of Formula I
Charged 8-chloro-5,10-dihydro-dibenzo[b,e][l,4] diazepine-11-one (10 g), toluene (150 ml) in RBF. The reaction mixture was cooled to 5-15°C. Added the solution of titanium

dropwise simultaneously at the temperature of 0-20°C. The reaction mass was stirred for 30 mins. The temperature of the reaction mass was raised to 110°C and stirred for 10 Hours at 110-115°C. After the completion the reaction mixture was cooled to 80-85°C followed by the addition of NaOH (20g) and reaction mixture was further stirred at 80-85°C. Reaction mixture was filtered at 80-85°C to remove inorganic salt. The wet cake was washed with hot toluene (100ml). The filtrate was collected and washed with DM water (100 ml x 2). The organic layer was separated and charged in RBF. Added charcoal (0.5g) and reaction mixture was stirred for 1 hour at 80-85°C. Reaction mixture was filtered from hyflo bed and washed with hot toluene (10 ml) at 80-85 °C. Toluene was distilled out under vacuum and degassed. Methanol (100 ml) and toluene (10 ml) were charged at 25-30°C. The reaction mixture was heated up to 60-65°C and stirred till the clear solution was obtained. The solution was filtered and washed with methanol (10ml) at 60-65°C. The filtrate was charged in RBF and distilled the methanol till half of the volume. The reaction mass was slowly cooled down to 20-25°C and further cooled to 0°C. The reaction mixture was stirred for 2 hours at 0-5°C and filtered. The wet cake was washed methanol (10 ml) and dried to get Clozapine (9 g) as light yellow powder.
Example-5; Purification of Clozapine
The crude clozapine (13.0 g) was washed with hot toluene (100ml). The filtrate was collected and washed with DM water (100 ml x 2). The organic layer was separated and charged in RBF. Added charcoal (0.5g) and reaction mixture was stirred for 1 hour at 80-85°C. Reaction mixture was filtered from hyflo bed and washed with hot toluene (10 ml) at 80-85°C. Toluene was distilled out under vacuum and degassed. To this methanol (100 ml) and toluene (10 ml) were charged at 25-30°C. The reaction mixture was heated up to 60-65°C and stirred till the clear solution was obtained. The solution was filtered and washed with methanol (10ml) at 60-65°C. The filtrate was charged in RBF and partially distilled the methanol. The reaction mass was slowly cooled down to 20-25°C and further cooled to 0°C. The reaction mixture was stirred for 2 hours at 0-5°C and filtered. The wet cake was washed methanol (10 ml) and dried to get Clozapine (10 g) as light yellow powder.
Example-6; Synthesis of Crystalline Clozapine

Charged Methanol (100 ml) to Clozapine (13.0 g) and heated the reaction mass. Added activated carbon slurry in reaction mass. Prepared the Hyflo bed in methanol and filtered the reaction mass through it with methanol wash. Distilled out methanol from reaction mass under vacuum and cooled the reaction mass. The reaction mass was dried through centrifuge with methanol wash to obtain wet cake. The wet cake was dried to get crystalline clozapine (10.0 g).
Example-6; Synthesis of Crystalline Clozapine
Charged Ethylacetate (80 ml) to Clozapine (13.0 g) and heated the reaction mass. Added activated carbon slurry in reaction mass. Prepared the Hyflo bed in methanol and filtered the reaction mass through it with ethylacetate wash. Distilled out ethylacetate from reaction mass under vacuum and cooled the reaction mass. The reaction mass was dried through centrifuge with ethylacetate wash to obtain wet cake. The wet cake was dried to get crystalline clozapine (10.0 g).

WE CLAIM:

1. A process for the preparation of clozapine of Formula I or pharmaceutically acceptable
salts, hydrates thereof,
N

CI
Formula I
wherein said process comprising the steps of:
a) treating 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one with N-methylpiperazine in presence of suitable solvent and catalyst to get clozapine;
b) optionally, purifying the clozapine in suitable solvent; and
c) optionally, converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.
2. The process as claimed in claim 1, wherein said process comprises the steps of:
a) treating 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one with N-methylpiperazine and catalyst in the presence of anisole and suitable solvent to get clozapine;
b) optionally, purifying the clozapine in suitable solvent; and
c) optionally, converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.
3. The process as claimed in claim 1, wherein said process comprises the steps of:
a) treating 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one with N-methylpiperazine and catalyst in the absence of anisole and suitable solvent to get clozapine;
b) optionally, purifying the clozapine in suitable solvent; and
c) optionally, converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.

4. The process as claimed in claim 1, wherein said anisole and suitable solvent is present
in the molar ratio of 0: 1 to 0.2: 1.
5. A process for the preparation of clozapine or pharmaceutically acceptable salts,
hydrates thereof, wherein said process comprising the steps of:
a) dissolving titanium tetrachloride in a suitable solvent to get a solution;
b) dissolving 8-chloro-5,10-dihydro-llH-dibenzo[b,e][l,4]-diazepin-ll-one in suitable solvent, optionally in presence of anisole to get a solution;
c) simultaneously adding N-methypiperazine and solution of step a) to the solution of step b);
d) heating the reaction mixture;
e) isolating to get clozapine; and
f) optionally purifying the clozapine in suitable solvent; and
g) optionally converting the clozapine to pharmaceutically acceptable salt or hydrates thereof.
6. A process for the purification of clozapine or pharmaceutically acceptable salts,
hydrates thereof, wherein said process comprising the steps of:
a) dissolving clozapine in a suitable solvent; and
b) isolating pure clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof.

7. The process as claimed in claim 6, wherein the solvent is selected from hydrocarbons, alcohols or mixture thereof.
8. A process for preparation of crystalline clozapine or pharmaceutically acceptable salts, hydrates thereof, wherein said process comprising the steps of:

a) dissolving clozapine in a suitable solvent; and
b) optionally adding anti-solvent; and
c) isolating crystalline clozapine of Formula I or pharmaceutically acceptable salts, hydrates thereof.
9. A process for the preparation of an amorphous solid dispersion of clozapine or

a) providing a solution of clozapine or pharmaceutically acceptable salts, hydrates thereof in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of clozapine or pharmaceutically acceptable salts, hydrates thereof.
10. The process as claimed in claim 1, wherein said clozapine of Formula I is substantially free of impurities of Formula A, B, C, D and N-oxide impurity, wherein each impurity is less than about 0.15% w/w.