FIELD OF THE INVENTION
The present invention relates novel synthesis of an Antipsychotic drug.
The present invention particular relates to novel synthesis of Clozapine which is a 'atypical' antipsychotic drug.
The present invention further relates to novel synthesis of Clozapine using novel intermediates.
The present invention further relates to an improved process for the preparation of Clozapine which is highly cost effective, commercially feasible & industrially advantageous.
BACKGROUND OF THE INVENTION
Clozapine is a tricyclic dibenzodiazepine derivative which is a atypical antipsychotic drug. The chemical name of Clozapine is 8-chloro-l l-(4-methyl-l-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine. The structural formula is:
Analytical Profiles of Drug Substances and Excipients 1993 discloses a process for the preparation of Clozapine which involves the reaction of anthranilic acid with nitro intermediate followed by reduction and cyclization to give Clozapine. The process is given in the scheme below:

The main drawback of the above invention is the cost of starting material and also the narcotic effect of Anthranilic acid. The use of Anthranilic acid in the preparation of Clozapine may not be suggested due to its narcotic properties. Anthranilic acid and its derivatives are widely recognized to show narcotic effects. Hence, it needs to develop the process for the preparation of Clozapine using other than Anthranilic acid as a raw material or starting material.
The present inventors have developed novel as well as improved process for the preparation of Clozapine which results in greater efficiency than the prior art processes with higher product purity.
OBJECT OF THE INVENTION
The main object of the invention is to provide novel process for the preparation of Clozapine using simple and cost effective novel intermediates.
The further object of the invention is to provide a simple, cost effective, improved and robust process for the preparation of Clozapine of Formula-I yielding at a high yield with high purity without formation of undesired impurities.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel process for the preparation of Clozapine of Formula-I
wherein Ri is amino protecting group to Clozapine.
In a preferred aspect, the present invention provides novel process for the preparation of Clozapine of Formula-1
or its salts, which comprises,
a) Reacting compound of Formula-Ill

wherein Ri is amino protecting group, with compound of Formula-FV
wherein R| is as defined above, b) Converting compound of Formula-II to Clozapine or its salt.
In another preferred aspect, the present invention provides novel process for the preparation of Clozapine of Formula-I
or its salts, which comprises,
a) Reducing compound of Formula-V
in the presence of a suitable reducing agent in a solvent to give compound of Formula-Ill

wherein Ri is amino protecting group, b) Reacting compound of Formula-Ill with compound of Formula-IV
wherein R( is as defined above, c) Converting compound of Formula-II to Clozapine or its salt.
In yet another preferred aspect, the present invention provides novel process for the preparation of Clozapine of Formula-I
or its salts, which comprises,
a) Reacting compound of Formula-VI

i ifiiuuia- v i
with amino protecting agent to give compound of Formula-V
wherein Ri is amino protecting group, b) Reducing compound of Formula-V in the presence of a suitable reducing agent in a solvent to give compound of Formula-Ill
Wherein Rj is amino protecting group c) Reacting compound of Formula-Ill with compound of Formula-IV .
Wherein Rj is as defined above, d) Converting compound of Formula-II to Clozapine or its salt.
In yet another preferred aspect, the present invention provides novel process for the preparation of Clozapine of Formula-I

or its salts, which comprises,
a) Reacting compound of Formula-VII
b) Reacting compound of FormuIa-VI with amino protecting agent to give compound of Formula-V
wherein Ri is amino protecting group, c) Reducing compound of Formula-V in the presence of a suitable reducing agent in a solvent to give compound of Formula-Ill
i ui 111 uia 111
Wherein R| is amino protecting group d) Reacting compound of Formula-Ill with compound of Formula-IV

wherein Ri is as defined above, e) converting compound of Formula-II to Clozapine or its salt.
In yet another preferred aspect, the present invention provides compounds of Formulae II, III and V
Wherein R| is amino protecting group.
In yet another preferred aspect, the present invention provides an alternate and improved process for the preparation of Clozapine using 2-halobenzoic acid as a raw material characterized in that it comprises reacting compound of Formula-VII
with 2-halobenzoic acid in a solvent and optionally the reaction may be performed in the presence of a catalyst and a base.

In yet another preferred aspect, the present invention provides an alternate and improved process for the preparation of Clozapine of Formula-I
or its salts, which comprises,
a) Reacting compound of Formula-VII
with 2-halobenzoic acid in the presence of base, solvent and optionally in the presence of a catalyst to give compound of Formula-VIa
b) Reducing compound of Formula-VIa in the presence of a suitable reducing agent in a solvent to give compound of Formula-Ilia
c) Cyclizing compound of Formula-IIIa in the presence of a suitable agent to give
compound of Formula-IIIb
n

Formula-IIIb d) Reacting compound of Formula-IIIb with compound of Formula-IV
to give Clozapine or its salts.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an novel process for the preparation of Clozapine or its salts
The inventors of the present invention have developed a novel approach a well as the improved process for the preparation of Clozapine which involves the use of simple and cost effective raw materials, wherein the starting material used in the present invention are non¬narcotic which are available commercially.
The improved process according to the present invention involves the less number of steps when compared to the prior art process, and also the Clozapine prepared according to the improved process does not contain any impurities more than prescribed levels. Further, the process involves less number of solvent extractions which gives good yield and quality of the product.
By adopting the both novel and improved routes, the inventors, of the present invention have successfully developed the compound of Formula-I with good yield and high purity, the cost of the starting materials as used in the present invention such 2-halo benzoic

acid and halo benzene are very low and commercially viable comparatively with Anthranilic acid which is narcotic.
Amino protecting group as used in the present invention may be selected from acetyl, carbobenzyloxy (cbz), tert-butyloxycarbonyl (boc), p-methoxybenzyl carbonyl (moz or meoz), 9-fluorenylmethyloxycarbonyl (fmoc), acetyl (ac), benzoyl (bz), benzyl (bn), benzyl carbamate, p-methoxybenzyl (pmb), 3,4-dimethoxybenzyl (dmpm), p-methoxyphenyl (pmp), tosyl (ts), sulfonamides. Preferably acetyl.
Solvent as used in the present invention is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, dimethylsulfoxide, dimethylacetamide, dimethyl formamide, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, ether solvents, di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert- butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene, benzene, toluene, xylene, heptane, hexane, cyclohexane, acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone, ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and their mixtures thereof.
Reducing agent as used in the present invention may be selected from Pd/C, Raney Nickel, Iron/acid, Iron/Lewis acids, Zinc, SnCI2l Na2S, UAIH4 and Na2S204.
Catalyst as used in the present invention may be selected from cuprous oxide, cupric oxide, cuprous iodide, cuprous bromide, cupric bromide, cuprous chloride, cupric chloride.
The present invention provides novel process for the preparation of Clozapine of Formula-I

or its salts, which comprises converting compound of Formula-IIA
to Clozapine.
In a preferred embodiment, the present invention provides novel process for the preparation of Clozapine of Formula-I
or its salts, which comprises,
a) Reacting compound of Formula-IIIA
with compound of Formula-I V

b) Converting compound of Formula-IIA to Clozapine or its salt.
In another preferred embodiment, the present invention provides novel process for the preparation of Clozapine of Formula-I
or its salts, which comprises,
a) Reducing compound of Formula-VA
in the presence of a suitable reducing agent in a solvent to give compound of Formula-IIIA
b) Reacting compound of Formula-HIA with compound of Formula-IV

to give compound of Formula-IIA
c) Converting compound of Formula-IIA to Clozapine or its salt.
In yet another preferred embodiment, the present invention provides novel process for the preparation of Clozapine of Formula-I
or its salts, which comprises,
a) Reacting compound of Formula-VI
with amino protecting agent to give compound of Formula-VA

b) Reducing compound of Formula-VA in the presence of a suitable reducing agent in a solvent to give compound of Formula-IIIA
c) Reacting compound of Formula-IIIA with compound of Formula-IV
d) Converting compound of Formula-IIA to Clozapine or its salt.
In yetanother preferred embodiment, the present invention provides novel process for the preparation of Clozapine of Formula-I
or its salts, which comprises,
a) Reacting compound of Formula-VII

With halo benzene in the presence of a base to give compound of Formula-VI,
b) Reacting compound of Formula-VI with amino protecting agent to give compound of Formula-VA
c) Reducing compound of Formula-VA in the presence of a suitable reducing agent in a solvent to give compound of Formula-IJIA
d) Reacting compound of Formula-IIIA with compound of Formula-IV

e) Converting compound of Formula-IIA to Clozapine or its salt.
In yet another preferred embodiment, the present invention provides compounds of Formulae 11 A, MA and VA
In yet another preferred embodiment, the present invention provides an alternate and improved process for the preparation of Clozapine using 2-chlorobenzoic acid .as a raw material characterized in that it comprises reacting compound of Formula-VII
In yet another preferred embodiment, the present invention provides an alternate and improved process for the preparation of Clozapine of Formula-I

or its salts, which comprises,
a) Reacting compound of Formula-VII
with 2-chlorobenzoic acid in the presence of base, solvent and in the presence of a catalyst to give compound of Formula-Via
b) Reducing compound of Formula-VIa in the presence of a suitable reducing agent in a solvent to give compound of Formula-IIIa
c) Cyclizing compound of Formula-IIIa in the presence of a suitable agent to give compound of Formula-IIlb
d) Reacting compound of Formula-IIlb with compound of Formula-IV

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.
In a Clean & dry Round bottom flask fitted with Dean's stork condenser, 25gm of 4-chloro-2-nitro aniline, 15gm of 2-chlorobenzoic acid was taken in 200mLof O-Xylene stirred for 10-15 minutes and then added 20gm of anhydrous potassium carbonate(K.2C03) followed by lOgm of diisopropyl ethylamine base at room temperature with gentle stirring. Slowly heated the reaction mass temperature to reflux and collected the water. After completion of the reaction mass was quenched in Water and pH adjusted to 2-3.5 with Cone. Hydrochloric acid. The precipitated solid material was isolated by filtration to afford 20gm desired product.
In a Clean & dry Round bottom flask fitted with Dean's stork condenser, 25gm of 4-chloro-2-nitro aniline, 15gm of 2-chlorobenzoic acid was taken in 200mL of N,N-

Dimethylamine stirred for 10-15 minutes and then added 20gm of Anhydrous potassium carbonate(K2CC>3) followed by lOgm of diisopropyl ethylamine base at room temperature with gentle stirring. Slowly heated the reaction mass temperature to reflux and collected the Water. After completion of the reaction mass was quenched in Water and pH adjusted to 2-3.5 with Cone. Hydrochloric acid. The precipitated solid material was isolated by filtration to afford 20gm desired product.
In a Clean & dry Round bottom flask fitted with Dean's stork condenser, 25gm of 4-chloro-2-nitro aniline, 15gm of 2-chlorobenzoic acid was taken in lOOmL of N,N-Dimethylamine and lOOmL of O-xylene stirred for 10-15 minutes and then added 20gm of Anhydrous potassium carbonate(K2C03) followed by lOgm of diisopropyl ethylamine base at room temperature with gentle stirring. Slowly heated the reaction mass temperature to reflux and collected the Water. After completion of the reaction mass was quenched in Water and pH adjusted to 2-3.5 with Cone. Hydrochloric acid. The precipitated solid material was isolated by filtration to afford 20gm desired product.
In clean and dried Round bottom flask 5.0 gm of 2-(4-chloro-2-nitrophenylamino) benzoic acid (Formula-Via), 50mL of Acetone taken into an aqueous solution of sodium bicarbonate (7.5gm in 20 Ml of Water) at room temperature. Then added 10.0 gm of Sodium dithionate in lot wise (five lots) to the reaction mass at 40°C and maintain the reaction mass temperature for 60-70 minutes for completion of the reaction. The reaction mass was cooled to room temperature after TLC complies and removed the excess of Acetone under reduced

pressure; the resulting aqueous mass pH was adjusted to 2-3 with cone. Hydrochloric acid. The precipitated light brown colored solid was filtered and dried to yielded 4.0 gm (90.9%).
10 gm of 2-(4-chloro-2-nitrophenylamino) benzoic acid„ 200 mL of Water was taken in a 500mL Round bottom flask with gentle stirring at room temperature and then added 16.0gm of Iron powder as single lot or lot wise followed by 12.0 gm CaCl2 to the above reaction mass under stirring. The whole reaction mixture was heated to 90-100°C and maintained for 1-3 Hrs. Once TLC complies then the reaction mass was cooled to room temperature and filter through hyflo bed. The filtered Mother liquor pH was adjusted to 2-3 with cone. Hydrochloric acid. The precipitated light brown colored solid was filtered and dried to yield 8.0 gm of the title compound with 90%.
5.0 gm of 2-(2-amino-4-chlorophenylamino) benzoic acid and 12.5gm of Triethylamine was taken in 50 mL of Methylene chloride containing round bottom flask at room temperature. The reaction mass was stirred for 20 minutes at room temperature and then slowly added 6.0 gm of Ethyl chloroformate over a period of 20 minutes and maintained for 2 hours at room temperature. After completion of the reaction methylene chloride was distilled off and the residue obtained was diluted with 20mL of Water and stirred for 30 minutes, dried the material after filtration of the desired product yielded 4.0gm (86.95%).

In a lOOOmL round bottom flask 200 mL O-xylene and lOgm of 8-Chloro-l l-oxo-10, ll-dihydro-5H-dibenzo-l, 4-diazepine was taken at room temperature and stirred for 30 minutes. The reaction mass cooled to 10-15°C and added 9.7 mL (16.4gm) Titanium (IV) chloride in 20 mL of O-Xylene was added drop wise over a period of 30 minutes with constant stirring. The reaction mixture was heated to reflux and maintain for 3 hours. The reaction mass was then cooled to 10°C. 20gm of 1-Methylpiperizine was added to the reaction mass during a period of 30 minutes, and further it was maintained for 30-45 minutes at 10°C. The reaction mixture then heated to reflux for 4 hours. Check TLC 10% Methanol in chloroform (1:9). After completion of the reaction mass was distilled off to get the residue, it was partitioned between 2M Aq. Hydrochloric acid (300mL) and Ethyl acetate (300mL). Emulsion filter through hyflo bed and separate the layers and aq. Layer washed with Ethyl acetate ( 2 X 150 mL) and the separated Aqueous layer was adjusted pH with Sodium hydroxide (pH-14) and extracted with Ethyl acetate ( 3 X 150mL ), The combined organics were washed with Water (2 x 100ML), and followed by brine. The organic layer was distilled under reduced pressure, the optioned solid clozapine was crystalized in Acetone and IPE and yielded 80%.
In a Clean & dry Round bottom flask fitted with reflux condenser, 5gm of 4-chloro-2-nitro aniline, 25mL bromo benzene was taken and stirred for 10-15 minutes and then added 8 gm of Anhydrous potassium carbonate(K2C03) followed by 0.5 gm of Copper iodide base at room temperature with gentle stirring. Slowly heated the reaction mass temperature to reflux

and maintained for 12 hours. After completion of the reaction mass was quenched in Water, extracted with methylene chloride (3 X 15mL), the combined organics, washed with water (20mL), removed the solvent under reduced pressure to afford 4.5 gm desired product.
In a Clean & dry Round bottom flask fitted with reflux condenser, 5gm of N-(4-chloro-2-nitrophenyl) benzenamine, 0.5 gm Iodine was taken, added 12.0gm Acetyl chloride drop wise under gentle stirring for 10-15 minutes and then Slowly heated the reaction mass temperature to 50-55°C and maintained the reaction mass for 3 hours. After completion of the reaction mass was quenched in Water (50mL), extracted with methylene chloride (3 X 15mL), the combined organics, washed with water (20mL), removed the solvent under reduced pressure. The resulting material 4.5 gm desired product was as such taken for next step.
In clean and dried Round bottom flask 5.0 gm of N-(4-chloro-2-nitrophenyl)-N-phenylacetamide, 50mL of Methanol taken into at room temperature. Then added 15.0 gm of Sodium dithionate in lot wise (five lots) to the reaction mass at 50-55°C and maintain the reaction mass temperature for 120 minutes for completion of the reaction. The reaction mass was cooled to room temperature and filtered the reaction mass after TLC complies and removed the Methanol of under reduced pressure; the obtained organic residue was diluted with Water (50mL) and extracted with (3 X 25mL), the combined organics was washed with

brine and distilled the solvent. The crystalized dark brown colored solid was dried to yielded 4.0 gm (72.72%).