Claims:I/We Claims:
1. A process for the preparation of Clozapine of formula-1, comprising:
a) reacting 4-chloro-2-nitro aniline of formula-2 with 2-chloro benzoic acid
in presence of potassium carbonate, cupper iodide in dimethylformamide to provide formula-3 which is on in-situ reduction with Sodium dithionite to provide 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4

b) cyclizing 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4 in
the presence of an acid to provide 8-chloro-5,10-dihydro-11H-dibenzo [b,e][1,4]diazepin-11-one of formula-5

Formula-5,
c) reacting 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one of
formula-5 with N-methyl piperazine in presence titanium (IV) chloride in toluene to provide Clozapine of formula-1

Formula-1.

2. The process as claimed in claim 1, acid used in step-b) is selected from acetic acid, sulphuric acid, hydrochloric acid, phosphoric acid or mixtures thereof.

3. A process for the preparation of Clozapine of formula-1, comprising:
a) reacting 4-chloro-2-nitro aniline of formula-2 with 2-chloro benzoic acid
in presence of potassium carbonate, cupper iodide in dimethylformamide to provide formula-3 which is in-situ reduction with Sodium dithionite to provide 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4

b) converting 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4
to Clozapine of formula-1

Formula-1.

4. A process for the preparation of Clozapine of formula-1, comprising:
a) cyclizing 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4

Formula-4
in presence of sulfuric acid and acetic acid in water to provide 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one of formula-5

Formula-5,
b) converting 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one
of formula-5 to Clozapine of formula-1

Formula-1.

5. A process for the purification of Clozapine of formula-1, comprising:
a) dissolving compound of formula-1 in a solvent,
b) isolating substantially pure compound of formula-1.

6. The process as claimed in claim 5, solvent used in step-a) is selected from methanol or dichloromethane. , Description:Field of the invention:
The present invention relates to an improved process for the preparation of Clozapine of formula-1.

Formula-1
Background of the invention:
Clozapine is a tricyclic dibenzodiazepine derivative, chemically known as 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine.
Clozapine is a typical antipsychotic drug indicated for treatment-resistant schizophrenia and reducing suicidal behaviour in patients with schizophrenia or schizoaffective disorder.
US3539573 patent discloses the process for the preparation of Clozapine by reacting 2-amino-4-chloro-diphenylamine-2'-carboxylic acid (4''-methyl) piperazide with phosphoroxy chloride in presence of N,N-dimethylaniline.
Process described in US’573 patent is shown in the following scheme

The above said process has some disadvantages i.e., usage of benzene and phosphoroxy chloride (POCl3) in the process. Benzene is a carcinogenic solvent. POCl3 is highly corrosive chemical and handling in the large scale is very difficult. Also the yield of the reaction is very low. By considering all the above demerits, the above said process is not viable on commercial scale.
US3962248 patent discloses the process for the preparation of Clozapine by reacting 8-chloro-10,11-dihydro-11-oxo-5H-dibenzo [b,e][1,4]-diazepine with N-methyl piperazine in presence of titanium tetrachloride in chlorobenzene, anisole, toluene or mixtures thereof.
Process described in US’248 patent is shown in the following scheme

US20100166887A1 patent disclosed the process for the preparation of Clozapine.
Process disclosed in above patent is shown in the following scheme.

IN338799 patent describes the process for the preparation of Clozapine by cyclizing 2-(2-amino-4-chlorophenylamino) benzoic acid in presence of alkyl chloroformates followed by reacting with N-methyl piperazine in presence of titanium (IV) chloride.
Process described in above patent is shown in the following scheme

Alkyl chloroformate is corrosive chemical usage in large scale is not acceptable hence the process is not viable on commercial scale.
The prior art processes have some disadvantages including, low product yield, usage of hazardous, toxic, expensive reagents and solvent like benzene, phosphoroxy chloride, Alkyl chloroformate in the reaction, multiple step processes and produces huge quantity of effluent and inorganic waste in the process. These disadvantages make the processes not suitable in large scale production.
Thus, there remains a need to develop an improved process for the preparation of Clozapine, which is simple, economic and industrially viable process with excellent yields and good quality.
The present inventors have developed an improved industrially viable process which does not involve the usage of any toxic and/or costly solvents or reagents and critical workup procedures. Accordingly, the present invention provides an improved process for the preparation of Clozapine, which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations with excellent yields and good quality.
Summary of the invention
The first embodiment of the present invention provides a process for the preparation of Clozapine of formula-1.
The second embodiment of the present invention provides a process for the preparation of Clozapine of formula-1.
The third embodiment of the present invention provides a process for the preparation of Clozapine of formula-1.
The fourth embodiment of the present invention provides a process for the purification of Clozapine of formula-1.
Brief description of the drawings
Figure 1: Illustrates powder X-ray diffraction (PXRD) pattern of line form of Clozapine obtained according to Example-12.
Detailed description of the invention
The term "solvent" used in the present invention refers to "non polar solvents like “hydrocarbon solvents" selected from n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene or mixtures thereof; "ether solvents" selected from dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane or mixtures thereof; "ester solvents" selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof; "polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone or mixtures thereof; "chloro solvents" selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixtures thereof; "ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and thereof; "nitrile solvents" selected from acetonitrile, propionitrile, isobutyronitrile or mixtures thereof; "alcoholic solvents" selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or mixtures thereof; "polar solvents" selected from water or mixtures thereof.
The term "acid" used in the present invention selected from but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, methane sulfonic acid, para toluene sulfonic acid, ethane-1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, and thereof. The term “pharmaceutically acceptable salts” or “salts” described in hereinbefore are obtained by reacting compound with acid selected from the above description.
The term "base" used in the present invention selected from but not limited to inorganic acids selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tertiary butyl amine, benzyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide mixtures thereof.
The term "room temperature" as used in the present invention herein refers to the temperature in the range from about 25-35°C.
"Substantially pure" as used in the present invention herein refers to the compound of formula-1 is substantially free from the impurities and having purity ranges from about 99.0% to 99.9% as measured by a liquid chromatography method.

The first embodiment of the present invention provides a process for the preparation of Clozapine of formula-1, comprising:
a) reacting 4-chloro-2-nitro aniline of formula-2 with 2-chloro benzoic acid in
presence of a base, a catalyst and in a solvent to provide formula-3 which is on in-situ reduction with reducing agent to provide 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4

b) cyclizing 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4 to
provide 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one of formula-5

Formula-5,
c) reacting 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one of
formula-5 with N-methyl piperazine to provide Clozapine of formula-1

Formula-1
and optionally purifying the compound to provide substantially pure compound of Clozapine of formula-1.

In first aspect of first embodiment, base used in step-a) is selected from organic or inorganic base, preferably inorganic base, more preferably metal carbonates or metal bicarbonates; catalyst used in step-a) is metal iodide selected from but not limited to copper iodide, nickel iodide, zinc iodide, lithium iodide, potassium iodide or sodium iodide, preferably copper iodide; solvent used in step-a) is selected from but not limited to polar-aprotic solvent, preferably dimethylformamide.
In second aspect of first embodiment, reducing agent in step-a) is selected from sodium dithionite, sodium sulphide, sodium bisulfite or metal in presence of hydrogen wherein metal selected from but not limited to nickel, iron, palladium, platinum, preferably sodium dithionite,; the reaction temperature of step-a) ranges from about 15-110°C.
In third aspect of first embodiment, the amount of base used in step-a) is ranges from 0.7 to 3.0 mole equivalent with respect to compound of formula-2; the amount of metal iodide used in step-a) is ranges from 0.05 to 0.5 mole equivalent with respect to compound of formula-2; the amount of sodium dithionite used in step-a) is ranges from 1.0 to 3.0 mole equivalent with respect to compound of formula-2.
In fourth aspect of first embodiment, wherein step-b) cyclization can be done in presence of acid or by heating the mixture to elevated temperature ranging from about 70-150°C in a solvent selected from hydrocarbon solvents.
Wherein, acid in fourth aspect selected from inorganic acid or organic acid, preferably acetic acid, sulphuric acid, hydrochloric acid, phosphoric acid or mixtures thereof.
In fifth aspect of first embodiment, the amount of acid used in step-b) is ranges from 0.5 to 4.0 volumes with respect to compound of formula-4.
In sixth aspect of first embodiment, wherein step-c) is carried out in presence of titanium (IV) chloride in a solvent selected from hydrocarbon solvents, ketone solvents or polar solvents, preferably hydrocarbon solvents more preferably toluene.
In seventh aspect of first embodiment, the amount of titanium (IV) chloride in step-c) is ranges from 1.5 to 2.5 mole equivalent with respect to compound of formula-5; the amount of N-methyl piperazine used in step-c) is ranges from 2.0 to 4.0 mole equivalent with respect to compound of formula-5.
In eighth aspect of first embodiment of the present invention provides a process for the preparation of Clozapine of formula-1, comprising:
a) reacting 4-chloro-2-nitro aniline of formula-2 with 2-chloro benzoic acid in
presence of potassium carbonate, cupper iodide in dimethylformamide to provide formula-3 which is on in-situ reduction with Sodium dithionite to provide 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4,
b) cyclizing 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4 in
presence of sulfuric acid and acetic acid in water to provide 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one of formula-5,
c) reacting 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one of
formula-5 with N-methyl piperazine in the presence of titanium (IV) chloride in toluene media to provide Clozapine of formula-1 and optionally purifying the compound to provide substantially pure compound of Clozapine of formula-1.

The second embodiment of the present invention provides a process for the
preparation of Clozapine of formula-1, comprising:
a) reacting 4-chloro-2-nitro aniline of formula-2 with 2-chloro benzoic acid in
presence of a base, a catalyst and in a solvent to provide formula-3 which is on in-situ reduction with reducing agent to provide 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4

b) converting 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4
to Clozapine of formula-1

Formula-1.

In first aspect of second embodiment, base used in step-a) is selected from organic or inorganic base, preferably inorganic base, more preferably metal carbonates or metal bicarbonates; catalyst used in step-a) is metal iodide selected from but not limited to copper iodide, nickel iodide, zinc iodide, lithium iodide, potassium iodide or sodium iodide, preferably copper iodide; solvent used in step-a) is selected from but not limited to polar-aprotic solvent, preferably dimethylformamide.
In second aspect of second embodiment, reducing agent in step-a) is selected from sodium dithionite or metal in presence of hydrogen wherein metal selected from but not limited to nickel, iron, palladium, platinium, preferably Sodium dithionite; the reaction temperature of step-a) ranges from about from 15-110°C.
In third aspect of second embodiment, the amount of base used in step-a) is ranges from 0.7 to 3.0 mole equivalent with respect to compound of formula-2; the amount of metal iodide used in step-a) is ranges from 0.05 to 0.5 mole equivalent with respect to compound of formula-2; the amount of sodium dithionite used in step-a) is ranges from 1.0 to 3.0 mole equivalent with respect to compound of formula-2.
In fourth aspect of second embodiment 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4 can be converted to Clozapine of formula-1 by process according to the present invention or by other similar processes known in the art.
In fifth aspect of second embodiment of the present invention provides a
process for the preparation of Clozapine of formula-1, comprising:
a) reacting 4-chloro-2-nitro aniline of formula-2 with 2-chloro benzoic acid in
presence of potassium carbonate, cupper iodide in dimethylformamide to provide formula-3 which is on in-situ reduction with Sodium dithionite to provide 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4,
b) converting 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4
to Clozapine of formula-1.

The third embodiment of the present invention provides a process for the preparation of Clozapine of formula-1, comprising:
a) cyclizing 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4

Formula-4
to provide 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one of formula-5

Formula-5,
b) converting 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one of
formula-5 to Clozapine of formula-1

Formula-1.

In first aspect of third embodiment, wherein step-a) cyclization is carried out in presence of acid selected from inorganic acid or organic acid, preferably acetic acid, sulphuric acid, hydrochloric acid, phosphoric acid or mixtures thereof.
In second aspect of third embodiment, the amount of acid used in step-a) is ranges from 0.5 to 4.0 volumes with respect to compound of formula-4.
In third aspect of third embodiment 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one of formula-5 can be converted to Clozapine of formula-1 by process according to the present invention or by other similar processes known in the art.
In fourth aspect of third embodiment of the present invention provides a process for the preparation of Clozapine of formula-1, comprising:
a) cyclizing 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4 in
presence of sulfuric acid and acetic acid in water to provide 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one of formula-5,
b) converting 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one of
formula-5 to Clozapine of formula-1.
The fourth embodiment of the present invention provides a process for the purification of Clozapine of formula-1, comprising:
a) dissolving compound of formula-1 in a solvent,
b) isolating substantially pure compound of formula-1.

Dissolving compound in step-a) can be done by optionally heating the mixture to a temperature ranging from about 35°C to reflux temperature of the solvent used.
The solvent used in step-a) selected from chloro solvents, alcohol solvents or any of the mixtures thereof; “isolating” in step-b) refers to solvent removal by known techniques which are selected from distillation, decanting, filtration, centrifugation, evaporation, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, by combining with an anti-solvent; wherein anti-solvent is different from the solvent used in step-a), or by any other conventional methods known in the art. Dried the obtained solid, Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and thereof, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperature less than about 50°C, less than about 25°C, less than about 10°C, less than about 5°C, or any other suitable temperature, in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.

In first aspect of fourth embodiment of the present invention provides a process for the purification of Clozapine of formula-1, comprising:
a) dissolving compound of formula-1 in methanol,
b) cooling the mixture obtained in step-a) to 0-5ºC,
c) filtering the substantially pure compound of formula-1.

Further aspect of present invention the compound of formula-1 obtained by the above purification process is line in nature and is characterized by its PXRD pattern substantially in accordance with figure-1.

In second aspect of fourth embodiment of the present invention provides a process for the purification of Clozapine of formula-1, comprising:
a) dissolving compound of formula-1 in dichloromethane,
b) adding isopropyl alcohol to the solution obtained in step-a),
c) filtering the substantially pure compound of formula-1.

Further embodiment of the present invention the following impurities are well controlled during the synthesis of the Clozapine of formula-1, along with these impurities, the starting materials are also well controlled in Clozapine of formula-1 as per ICH guidelines.

Impurity A:

Impurity B:

Impurity C:

Impurity D:

Further embodiment of the present invention the obtained Clozapine of formula-1 is having the purity more than 99% by HPLC, preferably more than 99.5% by HPLC, more preferably about 99.9% by HPLC and controlled all the impurities below ICH limits.

The inventors of present invention have also carried out the in-situ preparation of 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4 from 4-chloro-2-nitro aniline of formula-2 in presence of sodium carbonate and potassium hydroxide along with potassium carbonate. But these reactions have some disadvantages. The reaction carried out in presence of sodium carbonate as base was a slow reaction, takes more time for the completion and yield of the reaction also low. The reaction carried out in presence of potassium hydroxide as base was little faster reaction but yield was low and also formation of impurities was observed during the reaction.

Advantages of the present invention:
• The process described in the present invention is simple, safe, economic, eco-friendly and suitable for the production of Clozapine of formula-1 on commercial scale with a high reproducibility.
• In-situ preparation of 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4 provide environment friendly and cost-effective process which avoids the usage of excess reagent, solvent, and also avoids the extra filtration and drying process. This makes the process suitable on commercial scale.
• Over all yield of the reaction of 2-(2-amino-4-chlorophenyl amino) benzoic acid of formula-4 in in-situ manner is more compared with reactions wherein the intermediates are isolated.
• Usage of commercially available reagents and solvent provides cost-effective process.
• Solvents used in the present invention are recycled and reused in the process.

The other embodiment of the present invention provides a method of treating a patients suffering from schizophrenia comprising administering to the patients with a therapeutically effective amount of Clozapine obtained by the process of the present invention.
In another embodiment of the present invention provides pharmaceutical composition/ formulation comprising Clozapine and pharmaceutically acceptable excipients wherein, the pharmaceutical acceptable excipients include (but are not limited to) binders, diluents, disintegrants, surfactants and lubricants. Suitable binders that can be include (but are not limited to) polyvinylpyrolidone, copovidone, starches such as pregelatinized starch, cellulose derivatives such as hydroxypropylmethyl cellulose, ethylcellulose, hydroxylpropyl cellulose and carboxymethyl cellulose and their salts, gelatine, acacia, agar, alginic acid, carbomer, chitosan, dextrates, cyclodextrin, dextrin, glycerol dibehenate, guargum, hypromellose, maltodextrin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, sodium alginate, sucrose, mixtures thereof and the like; suitable diluents that can be include (but are not limited to) anhydrous lactose, lactose monohydrate, modified lactose, dibasic calcium phosphate, tribasic calcium phosphate, microline cellulose, silicified microline cellulose, powdered cellulose, maize starch, pregelatinized starch, calcium carbonate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol starch, calcium lactate or mixtures of diluents; suitable disintegrants that can be include (but are not limited to) magnesium aluminometa silicate (or magnesium aluminum silicate), starch, pregelatinized starch, sodium starch glycolate, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, alginic acid, carboxy methyl cellulose sodium, sodium alginate, calcium alginate and chitosan; suitable lubricants that can be include (but are not limited to) magnesium stearate, stearic acid, palmitic acid, talc, and aerosil. Suitable surfactants that can be include (but are not limited to) polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene-polyoxy-propylene copolymer and sodium lauryl sulphate.

Various modes of administration of the pharmaceutical composition/ formulation of the invention can be selected depending on the therapeutic purpose for example tablets or suspensions preparations.

Starting materials utilized in the present invention are commercially available in the market (or) they can be prepared according to the any of the processes known in the prior art.

Powder X-ray power diffraction (PXRD) method of analysis:
PXRD analysis of the line form of Clozapine is carried out by using Bruker D8 advance X-ray powder diffractometer using Cu-Ka radiation of wavelength 1.54060A° and at continuous scan speed of 0.033°/min.

High Performance Liquid Chromatography (HPLC) analysis method:
Clozapine and its related substances of present invention were analysed by HPLC with the following chromatographic conditions:
Apparatus: A liquid chromatographic system is equipped with variable wavelength UV detector; Column: octadecylsilyl silica; 5μm (or) equivalent; Wavelength: 257 nm; Flow rate: 1.2 mL/min; Injection volume: 20 μL; Elution: Gradient; Diluent: methanol and water (80:20 V/V); Buffer: 2.0 g/L of monobasic potassium phosphate. Adjust with phosphoric acid (85%) to a pH o 2.4.
Mobile phase-A: mixture of acetonitrile, methanol, and buffer (1:1:8). Mobile phase-B: mixture of acetonitrile, methanol, and buffer (4:4:2).

The First, second and third embodiments of the present invention are schematically represented as follows:

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are for illustrative purposes only and in no way limit the scope of the present invention.

Examples:
Example-1: 2-(2-amino-4-chlorophenyl amino) benzoic acid
Potassium carbonate (100 g, 1.24 mole equivalent), copper iodide (22.5 g, 0.2 mole equivalent) and 2-chloro benzoic acid (91 g, 1.0 mole equivalent) were added to the mixture of 4-chloro-2-nitro aniline (100 g, 1.0 mole equivalent) in dimethyl formamide (200 ml) at room temperature. Heated the reaction mixture and stirred for 12 hours. Water followed by sodium dithionite (152 g, 1.5 mole equivalent) were added to the above reaction mixture at room temperature and stirred for the 30 minutes at same temperature. Reaction mixture was acidified with acetic acid and filtered the solid, dried to get the title compound.
Yield: 145.18 g (95.37%).
Example-2: 2-(4-chloro-2-nitrophenylamino) benzoic acid
Potassium carbonate (100 g, 1.24 mole equivalent), copper iodide (22.5 g, 0.2 mole equivalent) and 2-chloro benzoic acid (91 g, 1.0 mole equivalent) were added to the mixture of 4-chloro-2-nitro aniline (100 g, 1.0 mole equivalent) in dimethyl formamide (200 ml) at room temperature. Heated the reaction mixture and stirred for 12 hours. Water was added to the reaction mixture further the reaction mixture was acidified with acetic acid. Filtered the solid, dried to get the title compound.
Yield: 145 g (85.5%).
Example-3: 2-(2-amino-4-chlorophenyl amino) benzoic acid
Sodium dithionite (90 g, 1.5 mole equivalent) was added to mixture of sodium carbonate (55 g, 1.5 mole equivalent), water (300 ml) and 2-(4-chloro-2-nitrophenylamino) benzoic acid (100 g, 1.0 mole equivalent) at room temperature. Heated the reaction mixture to 50-55°C and stirred for 30 minutes at same temperature. Reaction mixture was acidified with acetic acid and filtered the solid, dried to get the title compound.
Yield: 75.56 g (84.18%).
Example-4: 2-(2-amino-4-chlorophenyl amino) benzoic acid
Sodium carbonate (93 g, 1.5 mole equivalent), copper iodide (22.5 g, 0.2 mole equivalent) and 2-chloro benzoic acid (91 g, 1.0 mole equivalent) were added to the mixture of 4-Chloro-2-nitro aniline (100 g, 1.0 mole equivalent) in dimethyl formamide (200 ml) at room temperature. Heated the reaction mixture and stirred for 12 hours. Water followed by sodium dithionite (152 g, 1.5 mole equivalent) were added to the above reaction mixture at room temperature and stirred for 30 minutes at the same temperature. Reaction mixture was acidified with acetic acid and filtered the solid, dried to get the title compound.
Yield: 122.91 g (80.74%).
Example-5: 2-(2-amino-4-chlorophenyl amino) benzoic acid
Potassium hydroxide (36 g, 1.1 mole equivalent), copper iodide (11.5 g, 0.1 mole equivalent) and 2-chloro benzoic acid (91 g, 1.0 mole equivalent) were added to the mixture of 4-Chloro-2-nitro aniline (100 g, 1.0 mole equivalent) in dimethyl formamide (200 ml) at room temperature. Heated the reaction mixture and stirred for 10 hours. Water followed by Sodium dithionite (152 g, 1.5 mole equivalent) were added to the above reaction mixture at room temperature and stirred the reaction mixture for 30 min at same temperature. Reaction mixture was acidified with acetic acid and filtered the solid, dried to get the title compound.
Yield: 117.22 g (77%).
Example-6: 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one
2-(2-amino-4-chlorophenyl amino) benzoic acid (100 g) was added to the mixture of aqueous solution of sulphuric acid (100 ml sulphuric acid in 200 ml water) and acetic acid (100 ml) at room temperature. Heated the reaction mixture and stirred for 6 hours. Cooled the reaction mixture to room temperature and basified with 5% sodium hydroxide solution. Filtered the solid and dried to get the title compound.
Yield: 86.84 kg (93.23%).
Example-7: 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one
2-(2-amino-4-chlorophenyl amino) benzoic acid (100 g) was added to the mixture of aqueous solution of hydrochloric acid (100 ml Conc. Hydrochloric acid in 200 ml water) and acetic acid (100 ml) at room temperature. Heated the reaction mixture and stirred for 8 hours. After completion of the reaction, cooled the reaction mixture to room temperature and basified with 5% sodium hydroxide solution. Filtered the solid and dried to get the title compound.
Yield: 81.24 kg (87.22%).
Example-8: 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one
2-(2-amino-4-chlorophenyl amino) benzoic acid (100 g) was added to xylene (300 ml) at room temperature. Reaction mixture was heated to reflex and stirred for 40 hours. After completion of the reaction, cooled the reaction mixture to room temperature. Filtered the solid and washed with 5% sodium hydroxide solution and dried to get the title compound.
Yield: 74.86 kg (80.37%).
Example-9: 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one
2-(2-amino-4-chlorophenyl amino) benzoic acid (100 g) was added to the mixture of xylene (300 ml) and sulphuric acid (10 ml) at room temperature. Reaction mixture was heated to reflex and stirred for 18 hours. After completion of the reaction, cooled the reaction mixture to room temperature and basified with 5% sodium hydroxide solution. Filtered the solid and dried to get the title compound.
Yield: 78.52 kg (84.30%).

Example-10: 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one
Potassium carbonate (100 g, 1.24 mole equivalent), copper iodide (23 g, 0.2 mole equivalent) and 2-chloro benzoic acid (91 g, 1.0 mole equivalent) were added to the mixture of 4-Chloro-2-nitro aniline (100 g, 1.0 mole equivalent) in dimethyl formamide (200 ml) at room temperature. Heated the reaction mixture and stirred for 12 hours. Water followed by Sodium dithionite (152 g, 1.5 mole equivalent) were added to the reaction mixture at room temperature and stirred the reaction mixture for 30 minutes at same temperature. Mixture of aqueous solution of sulphuric acid (300 ml sulphuric acid in 600 ml water) and acetic acid (200 ml) were added to above reaction mixture at room temperature. Heated the reaction mixture and stirred for 6 hours. After completion of the reaction, cooled to room temperature and basified with 10% sodium hydroxide solution. Filtered the solid and dried to get the title compound.
Yield: 80.56 kg (86.49%).
Example-11: Preparation of Clozapine of formula-1
Titanium tetrachloride (170 g, 2.19 mole equivalent) was added to the mixture of 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (100 g, 1.0 mole equivalent) in toluene (1000 ml) at 10-15°C and stirred the reaction mixture at same temperature for 30 minutes. Heated the reaction mixture to 105-110°C and stirred for 3 hours. N-methylpiperazine (122.5 g, 3 mole equivalent) was added to the above reaction mixture at 105-110 °C and stirred the reaction mixture at same temperature for 4 hours. After completion of the reaction, cooled the reaction mixture to room temperature and basified with 5% aqueous sodium hydroxide solution. Organic layer was washed with water. Heated the reaction mixture to 50-60°C and stirred for 20 minutes at same temperature. Filtered the reaction mixture through Hyflow bed and the filtrate was distilled under reduced pressure. Cooled the filtrate to room temperature and filtered the solid, dried to get the title compound.
Yield: 115.97 g (86.82 %); Purity: 99.5% by HPLC.

Example-12: Purification of Clozapine of formula-1
Clozapine (100 g) was dissolved in methanol (1 L) at 60-65°C and filtered through 0.2 micron filter. Clear filtrate was distilled under reduced pressure and then cooled to 0-5°C. Filtered the solid and dried to get the pure compound.
Yield: 96.13 g (96.13%); Purity: 99.9% by HPLC.
PXRD pattern of the above compound is illustrated in figure-1.
Example-13: Purification of Clozapine of formal-1
Clozapine (100g) was dissolved in dichloromethane (300 ml) and filtered through 0.2 micron filter. Isopropyl alcohol was added to the above obtained clear filtrate at room temperature and stirred for 10 min. Filtered the solid and dried to get pure compound.
Yield: 98.4 g (98.4%)