Field of invention:
The present invention relates to improved and novel processes for the preparation of metopimazine or its pharmaceutically acceptable salts. Metopimazine is chemically known as l-(3-[2-(methylsulfonyl)-10/f-phenothiazin-10-^yl]propyl) piperidine-4-carboxamide represented by the following structural formula-1.

Metopimazine (Vogalene*) is a dopamine D2 receptor antagonist that has been used in France for many years for the prevention and treatment of nausea and vomiting. It has not been approved in US and Europe.
Background of invention:
Metopimazine and process for their preparation was disclosed in DE 1092476. The disclosed process is schematically represented in the below scheme-1:

The disclosed process involves the reaction of methyl thioether (1) with sodium amide followed by acetic anhydride to provide an amide (2), which on oxidation with peracid followed by treatment with sodium hydroxide affords the phenothiazine (3). The

said intermediate-(3) on reaction with 3-chloro-l-bromo-propane provides the compound-(4), which on condensation with piperidine-4-carboxaniide provides metopimazine. The above process uses very strong base such as NaNH2 which is difficult to handle in a large scale process. Also as it is having high basicity it leads to formation by-products. In the acetylation process acetic anhydride is used which is difficult to procure commercially as well as with the required purity. As it has to be used in large excess, therefore it generates large quantities of acetic acid which contaminates the effluent. In the preparation of compound (3) by oxidation, meta-chloroperbenzoic acid is used which produces meta-chlorobenzoic acid as a byproduct which is not easily removed. Hence the yield and purity of the compound obtained is not satisfactory and the process cannot be scaled up to commercially level.
Hence it is advantageous to have improved or alternate/novel processes for the preparation of pharmaceutically important compounds like metopimazine with high yield and purity.
The present invention overcomes the disadvantages of the prior art process. The mam objective of the present invention is to provide an improved and novel process for the preparation of metopimazine which provides product with high yield and purity and also which is easy to scaleup.
Brief description of the invention:
The present invention relates to novel and improved processes for the preparation of metopimazine or its pharmaceutically acceptable salts.
The first aspect of the present invention is to provide a process for the preparation of 10-(3-halopropyl)-2-(methylthio)-10/^phenothiazine compounds of general formula-4, which comprises of reacting the 2-(methylthio)-10//-phenothiazine compound of formula-2 with 1,3-dihalo propane compounds of general fonnula-3 in presence of a suitable base or its aqueous solution and in presence or absence of a phase transfer catalyst in a suitable solvent to provide the compound of formula-4.

The second aspect of the present invention is to provide a process for the preparation of 10-(3-halopropyl)-2-(methylsulfonyl)-10//-phenothiazine of compounds of general formula-5, which comprises of oxidation of thel0-(3-halopropyl)-2-(methylthio)-10//-phenothiazine compounds of general formula-4 with a suitable oxidizing agent in a suitable solvent m presence or absence of a phase transfer catalyst.
The present invention further includes the 10-(3-halopropyl)-2-(methylthio)-10//-phenothiazine compounds of general formula-4 and its use as an intermediate in the preparation of metopimazine and its pharmaceutically acceptable salts.
The third aspect of the present invention is to provide a novel process for the preparation of metopimazine of compound of formula-1 through the compounds of general fonnula-4, which comprises of the following steps;
a) reacting the 2-(methylthio)-10//-phenothiazine compound of formula-2 with 1,3-dihalo propane compounds of general formula-3 in a suitable solvent in presence of a base to provide 10-(3-halopropyl)-2-(methylthio)-10//-phenothiazine compounds of general formula-4,
b) oxidizing the 10-(3-halopropyl)-2-(methylthio)-10//-phenothiazine compounds of general formula-4 with a suitable oxidizing agent in a suitable solvent in presence or absence of a phase transfer catalyst to provide 10-(3-halopropyl)-2-(methylsulfonyl)-10//-phenothiazine of compound of general formula-5,
c) reacting the compound of formula-5 with piperidine-4-carboxamide in presence of a suitable base in a suitable solvent to provide metopimazine compound of formula-1,
d) optionally purifying the compound of formula-1 using suitable solvent to provide the high pure metopimazine compoimd of formula-1
The fourth aspect of the present invention is provide a process for the purification of metopimazine compound of formula-1, which comprises of recrystallisation of formula-1 in a single solvent followed by recrystallisation from a mixture of solvents. Further the present invention includes a novel crystalline form of metopimazine compound of formula-1. The novel crystalline form of the present invention is characterized by its PXRD and DSC.

The fifth aspect of the present invention is to provide an improved process for the preparation of metopimazine compound of formula-1.
Brief Description of the Drawings:
Figure-1: Illustrates the powder X-ray diffractogram of crystalline metopimazine
compound of formula-1
Figure-2: Illustrates the DSC of crystalline metopimazine compound of formula-1.
Advantages of the present invention:
• The present invention uses mild inorganic like sodium hydroxide, potassium carbonate etc. and organic bases like triethyl amine, pyridine and the like in the place of sodium amide.
• Hydrogen peroxide is used in the place of meta-chloroperbenzoic acid eliminates the formation of meta-chlorobenzoic acid as by-product and as an impurity.
• Uses acetyl chloride in one mole ratio in the place of acetic anhydride which is taken excess, which leads to minimimi formation of acetic acid which decreases the load on the effluent.
• Toluene is used as a solvent which can be recovered and reused cutting down the cost of production and also reduces pollution.
• Provides a commercially viable and eco friendly process for the preparation of metopimazine or its pharmaceutically acceptable salts general formula-1.
Detailed description of the invention:
As used here in the term "alcoholic solvent" refers to methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; the term "ester solvents" refers to ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; the term "hydrocarbon solvents" refers to toluene, xylene, cyclohexane, hexane, heptane and the like; the term "chloro solvents" refers to methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like; "polar aprortic solvents" refers to dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and the like; the term "nitrile solvents" refers to acetonitrile and the like; "ketone solvents" refers to acetone, methyl isobutyl ketone and the like.

As used herein the term "inorganic base" refers to the bases selected from alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal hydroxide like sodium hydroxide, potassium hydroxide; alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate and the like; the term "organic base" refers to triethylamine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methyl morpholine and diisopropylethyl amine and the like.
As used herein the term "phase transfer catalyst" refers to tetraethylammonium p-toluenesulfonate, tetrapropyl ammonium trifluoromethanesulfonate, tetraphenyl phosphonium hexafluoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenyl phosponium chloride, benzyltriethyl ammonium chloride, benzyltrimethylammonium chloride, benzyltriphenylphosphonium chloride, benzytributylammonium chloride, butyl triethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide, methyltriphenylphosphonium bromide, methyl triphenylphosphonium iodide, phenyl trimethylammonium chloride, tetrabutylammonium hydroxide, tetrabutyl ammonium perchlorate, tetrabutylammonium bromide, tetrabutyl ammonium hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium tetra fluoroborate, tetrabutyl ammonium thiocyanate, tetraethylammonium hydroxide, tetraethylanunonium iodide, tetraethylammonium bromide, tetramethylammonium chloride, tetramethylammonium iodide, tetramethylammonium chloride, tetraoctyl ammonium bromide, tetraphenyl phosphonium bromide, tetrapropylammonium hydroxide, tetrapropylammonium bromide and tributylmethylammonium chloride.
The present invention relates to novel and improved processes for the preparation of metopimazine compound of formula-1.


Accordingly the first aspect of the present invention provides a proems for the preparation of 10-(3-haIopropyl)-2-(methylthio)-10//-phenothiazine the compounds of general fomiula-4,
Wherein X is a halogen,
which comprises of reacting the 2-(methylthio)-10/f-phenothiazine compound of
formula-2
with 1,3-dihalo propane compounds of general formula-3

Wherein X is a halogen which may be the same or different,
m presence of a suitable base selected from organic or inorganic bases or its aqueous solution in a suitable solvent selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or mixtures thereof, in presence or absence of phase transfer catalyst to provide the 10-(3-halopropyl)-2-(methylthio)-10//'-phenothiazine the compounds of general formula-4.
In a preferred embodiment, the present invention provides a process for the preparation of 10-(3-chloropropyl)-2-(methylthio)-10//-phenothiazine compound of formula-4a.


which comprises of reacting the 2-(methyhhio)-10//-phenothiazine compound of formula-2 with l-bromo-3-chloro propane compound of formula-3a in presence of aqueous sodium hydroxide and tetrabutyl ammonium bromide in toluene to provide 10-(3-chloropropyl)-2-(methylthio)-10//-phenothiazine compound of formula-4a.
The second aspect of the present invention provides process for the preparation of 10-(3-halopropyl)-2-(methylsulfonyl)-10/f-phenothiazine compounds of general formula-5

wherein X is a halogen
which comprises of oxidizing the 10-(3-halopropyl)-2-(methylthio)-10/f-phenothiazine
compounds of general formula-4,

with a suitable oxidizing agent selected from hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; in presence of catalyst like ammonium molybdate and in presence or absence of a phase transfer catalyst in a suitable solvent selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or mixtures thereof, to provide the compound of formula-5.
In a preferred embodiment, the process for the preparation of lO-(3-chloropropyl)-2-(methylsulfonyl)-10//-phenothiazine compoimd of formula-5a.


comprises of oxidizing the 10-(3-chloropropyl)-2-(methylthio)-10/f-phenothiazine compound of fonnula-4a,

with hydrogen peroxide in presence ammonium molybdate and tetra butyl ammonium bromide in chloroform to provide the 10-(3-chloropropyl)-2-(methylsulfonyl)-10//-phenothiazine compound of formula-5a.
Further the present invention provides a novel 10-(3-halopropyl)-2-(methylthio)-lO/f-phenothiazine compound of general formula-4, a novel intermediate used in the preparation of metopimazine or its pharmaceutically acceptable salts.

Wherein X is a halogen,
In a preferred embodiment of the present invention X is Chlorine, i.e., 10-(3-chloro
propyl)-2-(methylthio)-10//-phenothiazine compound formula-4a.
The third aspect of the present invention provides a novel process for the preparation of the metopimazine compound of formula-1 through the novel intermediate compound of formula-4, which comprises of
a) reacting the 2-(methylthio)-10//-phenothiazine compound of formula-2 with 1,3-dihalo propane compounds of general formula-3,

wherein X is a halogen which may be the same or different,
in presence of a suitable base selected from organic or inorganic bases or its aqueous
solutions in a suitable solvent selected from alcohols, esters, hydrocarbons, chloro.

polar aprotic, nitrile, ketone or mixtures thereof to provide the 10-(3-halopropyl)-2-(methylthio)-10//-phenothiazine compounds of general formula-4,

b) oxidizing the compounds of general formula-4 with a suitable oxidizing agent in
selected from hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic
acid, perbenzoic acid, m-chloro perbenzoic acid and the like; in presence of catalyst
like ammonium molybdate and in presence or absence of a phase transfer catalyst in a
suitable solvent selected from alcohols, esters, hydrocarbons, chloro, polar aprotic,
nitrile, ketone or mixtures thereof, to provide the compound of formula-S,
Formula-5
c) reacting the compounds of general formula-5 with piperidine-4-carboxamide in
presence of suitable base selected from organic or inorganic base in a suitable solvent
selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or
mixtures thereof to provide the metopimazine compound of formula-1.
In a preferred embodiment of the present invention, the novel process for the preparation of the metopimazine compound of formula-1 comprises of
a) reacting the 2-(methylthio)-10//-phenothiazine compound of formula-2 with l-bromo-3-chloro propane compound of formula-3a in presence of aqueous sodium hydroxide and tetrabutyl ammonium bromide in toluene to provide 10-(3-chloropropyl)-2-(methylthio)-10i/-phenothiazine compound of formula-4a,
b) oxidizing compound of formula-4a vith hydrogen peroxide in presence ammonium molybdate and tetrabutyl ammonium bromide in chloroform to provide 10-(3-chloropropyl)-2-(methylsulfonyl)-10//-phenothiazine compound of formula-5a.

c) reacting the compound of formula-5a with piperidine-4-carboxaniide in presence of triethyl amine in a suitable alcoholic solvent to provide the metopimazine compound of formula-1,
The fourth aspect of the present invention is provide a process for the purification of metopimazine compound of formula-1, which comprises of the following steps,
a) dissolving the crude metopimazine in alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile and ketone,
b) subjecting the solution to carbon treatment,
c) filtering the solution through hyflow and washing with corresponding solvent,
d) distilling off the solvent completely imder reduced pressure,
e) suspending the residue in a mixture of solvent selected fi:om alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile and ketone,
f) heating the reaction mixture to reflux,
g) cooling the reaction mixture,
h) filtering the solid and washing with mixture of methanol and ethyl acetate, i) drying the solid to get the pure metopimazine compound of formua-1.
In a preferred embodiment, a process for the purification of metopimazine compound of formula-1 comprises of the following steps,
a) dissolving the crude metopimazine in a methylene chloride,
b) subjecting the solution to carbon treatment,
c) filtering the solution through hyflow and washing with methylene chloride,
d) distilling off the solvent completely under reduced pressure,
e) suspending the residue in a mixture of methanol and ethyl acetate,
f) heating the reaction mixture to reflux,
g) cooling the reaction mixture,
h) filtering the solid and washing with mixture of methanol and ethyl acetate, i) drying the solid to get the pure title compound.
In a preferred embodiment, a process for the purification of metopimazine compound of formula-1 comprises of the following steps, a) dissolving the crude metopimazine in a methylene chloride.

b) subjecting the solution to carbon treatment,
c) filtering the solution through hyflow and washing with methylene chloride,
d) distilling off the solvent completely under reduced pressure,
e) suspending the residue in a mixture of acetone and acetonitrile,
f) heating the reaction mixture to reflux,
g) cooling the reaction mixture,
h) filtering the solid and washing with mixtiire of acetone and acetonitrile,
i) drying the solid to get the pure title compound.
As used herein the term "crude" refers to the compoimd obtained directly after the reaction may be in the form of solid, residue or oily residue or the compound before purification.
Further the present invention includes a novel crystalline form of metopimazine compound of formula-1. The novel crystalline form of the present invention is characterized by its PXRD having peaks at 4.37, 8.75, 9.76, 13.16, 17.59, 19.10, 19.62, 19.92, 19.92, 21.73, 22.05, 26.05 and 31.06 ± 0.2 degrees 20 and by its differential scanning calorimetry showing endothermic peak at 173.65°C. The novel crystalline form of metopimazine compound of formula-1 of the present invention is advantageous, as it is free flowing solid with high purity and stability and can be directly used for formulation as an active pharmaceutical ingredient.
The fifth aspect of the present invention provides an improved process for the preparation of the metopimazine compound of formula-1, which comprises of a) acylating the 2-(methylthio)-10/f-phenothiazine compound of formula-2

with a suitable acylating agent like acetyl chloride in a suitable solvent selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or mixtures thereof, preferably hydrocarbon solvent, to provide the compound of formula-6,

optionally recrystallisation of compound of formula-6 from a suitable hydrocarbon solvent provides pure compound of formula-6,

b) oxidizing compound of formula-6 with oxidizing agent selected from hydrogen
peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid,
m-chloro perbenzoic acid and the like; in presence of a catalyst like ammonium
molybdate in a suitable solvent selected from alcohols, esters, hydrocarbons, chloro,
polar aprotic, nitrile, ketone or mixtures thereof and in presence or absence of phase
transfer catalyst followed by hydrolysis of the obtained compound with suitable
aqueous basic solutions, provides the 2-(methylsulfonyl)-10//-phenothiazine
compound of formula-7.

c) reacting the compound of formula-7 v^th 1,3-dihalo compound of general formula-3,

wherein X is a halogen which may be the same or different, in presence of suitable base selected from inorganic or organic base or its aqueous solution, in a suitable solvent selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or mixtures thereof, preferably hydrocarbon solvents, provides the compound of formula-5.


d) reacting the compound of formula-5 with piperidine-4-carboxamide in presence of a suitable base selected from inorganic or organic bases, preferably organic base, in a suitable solvent selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or mixtures thereof, preferably alcoholic solvents to provide the metopimazine compound of formula-1,
e) optionally purifying the compound of formula-1 using a suitable solvents selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or mixtures thereof to provide the pure compound of formula-1.
In a preferred embodiment, improved process for the preparation of the metopimazine compound of formula-1 comprises of the following steps;
a) acylating the 2-(methylthio)-10//-phenothiazine compound of formula-2

with acetyl chloride in toluene, followed by crystallization of the obtained compoimd in cyclohexane to provide the compoimd of formula-6,

b) oxidizing the compound of formula-6 with hydrogen peroxide in presence of a ammonium molybdate and tetrabutylammoniumbromide in chloroform, followed by hydrolysis of the obtained compound with aqueous sodium hydroxide provides the 2-( methylsulfonyl)-10//-phenothiazine compound of formula-7,
c) reacting the compound of formula-7 with 1,3-dibromo propane compound of formula-3b in presence of aqueous sodium hydroxide and tetrabutylammoniumbromide in toluene provides the 10-(3-bromopropyl)-2-(methylsulfonyl)-10//-phenothiazine compound of formula-5b.


d) reacting the compound of formula-5b with piperidine-4-carboxamide in presence of
triethylamine in isopropyl alcohol to provide the metopimazine compound of
formula-1,
e) optionally purifying the compound of fonnula-1 using a suitable solvents selected
from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or mixtures
thereof to provide the pure compound of formula-1.
Metopimazine or its pharmaceutically acceptable salts of the present invention can be further micronized or milled to get the desired particle size.
The present invention schematically represented by the following scheme:



In the present invention the impurities are controlled to the levels which meet the
specifications of ICH guidelines.
Related substances of the metopimazine were analyzed by HPLC using the following
conditions:
Apparatus: A liquid chromatograph is equipped with variable wavelength UV-detector. Column: Symmetry Cig 250 x 4.6 mm, 5 ^un or equivalent; Flow rate: 1.0 ml/min; Wavelength: 266 nm; Temperature: 25°C; Injection volume 20 ^L; Run time 25 min; Elution: gradient; and using buffer and acetonitrile in 90:10 v/v ratio and aqueous acetonitrile: water in 90:10 v/v as mobile phases. Buffer is aqueous solution of triethylamine.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
ExampIe-1: Preparation of 10-(3-chlorpropyI)-2-(methylthio)-10i7-phenothiazine
compound of formula-4a:
A mixture of 2-(methylthio)-10H-phenothiazine (50 grams), toluene (IL) and aqueous sodium hydroxide solution (32.6 grams in 50 ml of water) was heated to reflux. Tetrabutyl ammonium bromide (2 grams), followed by l-bromo-3-chloro-propane (320 grams) was added to the reaction mixture and refluxed. After completion of the reaction, reaction mixture was cooled to 25-30°C and quenched with water. Both aqueous and organic layers were separated. Organic layer was washed with sodium bicarbonate solution followed by water and then dried with sodivmi sulfate. The solvent from the organic layer was distilled ofT completely under reduced pressure to get the title compound. Yield: 65 grams.
Example-2: Preparation of 10-(3-chloropropyI)-2-(methylsulfonyl)-10H-phenothiazine compound of formula-5a:
A solution of ammonium molybdate (0.5 grams) in 30% hydrogen peroxide solution (14 grams) was added to a mixture of 10-(3-chloropropyl)-2-(methylthio)-10i?-phenothiazine of formula-4a (20 grams), tetrabutyl ammonium bromide (0.4 grams) and chloroform (100 ml) at 25-30°C and stirred. After completion of the reaction, reaction mixture was cooled to 15-20°C and quenched with aqueous sodium sulfite solution. Both organic and aqueous layers were separated. Organic layer was washed with water and then dried with sodium sulfate. The solvent from the organic layer was distilled off completely imder reduced pressure to get the title compound. Yield: 21 grams.

ExanipIe-3: Preparation of metopimazine of formula-1:
A mixture of lO-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine of fonnula-Sa (20 grams), triethyl amine (41.9 ml), piperidine-4-carboxamide (51.5 grams), and isopropyl alcohol (150 ml) was heated to reflux. After completion of the reaction, it was cooled to 50-60°C and the solvent was distilled off completely under reduced pressure. Water (100 ml) followed by ethyl acetate (100 ml) was added to the obtained residue at 25-30°C and then acidified it with hydrochloric acid and stirred. The organic and aqueous layers were separated and aqueous layer was basified with sodium carbonate solution. The reaction mixture extracted into methylene chloride, dried it with sodium sulphate and then distilled off under reduced pressure. Ethyl acetate (20 ml) was added to the obtained solid at 25-30°C and stirred for 60 minutes. The solid was filtered, washed with ethyl acetate and then dried to get the title compound. Yield: 1.2 grams.
ExampIe-4: Preparation of l-(2-(methylthio)-10jff-phenothiazin-10-yl)ethanone of formula-6:
Acetyl chloride (639.8 grams) was added to a solution of 2-(methylthio)-10H-phenothiazine (250 grams) in toluene (2.5 L) at 25-30°C, heated to 50-55°C and stirred. After completion of the reaction, reaction mixture was cooled to 25-30°C and poured into ice cold water and stirred for 45 minutes. The organic and aqueous layers were separated and organic layer was washed with sodium bicarbonate solution followed by water. Organic layer was distilled off completely under reduced pressure and cyclohexane (1250 ml) was added to obtained residue at 25-30°C. The reaction mixture was stirred for 1 hour at 25-30°C. The solid obtained was filtered, washed with cyclohexane and dried to get the title compound. Yield: 254 grams.
Example-5: Preparation of 2-(methylsulfonyl)-10H-phenothiazine of formula-7:
A solution of ammonium molybdate (0.5 grams) in 30% hydrogen peroxide (197.2 grams) was added to mixture of l-(2-(methylthio)-10//-phenothiazin-10yl) ethanone of formula-6 (250 grams), tetrabutylammoniumbromide (5.6 grams) in

chloroform (1250 ml) at 25-30°C and stirred. After completion of the reaction, reaction mixture was cooled to 15-20°C and quenched with 10% sodium sulfite solution. Both the organic and aqueous layers were separate. Organic layer was distilled off under reduced pressure and methanol (3.75 L) was added to the obtained solid at 25-30°C. Sodium hydroxide (3.48 grams) was added to the reaction mixture at 25-30''C and stirred for 1 hour. The unwanted solid was filtered off and washed with methanol. The filtrate was added to water (20 liters) slowly and stirred for 2 hours at 15-20°C, The solid obtained was filtered, washed with water and dried to get the title compoimd. Yield: 82 grams.
£xample-6: Preparation of 10-(3-bromopropyl)-2-(methylsulfonyl)-10J7-phenothiazine of formula-5b:
A mixture of 2-(methylsulfonyl)-10^-phenothiazine of formula-7 (80 grams), aqueous sodium hydroxide (44.5 grams in 80 ml of water) and toluene (1.6 liters) was heated to refiux and stirred for an hour. 1,3-dibromo propane (232.8 grams) followed by tetrabutyl anmionium bromide (6.54 grams) was slowly added to the reaction mixture at reflux and stirred. After completion of the reaction, the reaction mixture was cooled to 25-30°C and stirred for an hour. The reaction mixture was filtered and washed it with toluene then the filtrate was washed with water. Organic layer was dried over sodium sulfate and then distilled off the solvent completely under reduced pressure to get the title compound. Yield: 122 grams.
Example-?: Preparation of metopimazine compound of formula-1
A mixture of 10-(3-bromopropyl)-2-(methylsulfonyl)-10H-phenothiazine of formula-5b (20 grams), triethyl amine (20.3 grams), piperidine-4-carboxamide (25.7 grams), and isopropyl alcohol (800 ml) was heated to reflux temperature and stirred. After completion of the reaction, reaction mixture was cooled to 50-60°C and the solvent was distilled off completely under reduced pressure. Water (100 ml) followed by ethyl acetate (100 ml) was added to the obtained residue at 25-30°C and then acidified it with hydrochloric acid and stirred. The organic and aqueous layers were separated and

aqueous layer was basified with sodium carbonate solution. The reaction mixture extracted into methylene chloride, dried it with sodium sulphate and then distilled off under reduced pressure. Ethyl acetate (50 ml) was added to the obtained solid at 25-30°C and stirred for 60 minutes. The solid was filtered, washed with ethyl acetate and then dried to get the title compound. Yield: 12.5 grams.
Example-8: Purification of metopimazine of formula-1:
Metopimazine (1 grams) was dissolved in methylene chloride (30 ml) and subjected to carbon treatment. The reaction mixture was filtered through hyflow and washed with methylene chloride. The filtrate was distilled off completely under reduced pressure, 10% of methanol in ethyl acetate (27 ml) was added to the obtained residue at 25-30°C. The reaction mixture was heated to reflux and stirred the reaction mixture for 15 minutes. The reaction mixture was cooled to 5°C and stirred for an hour. The solid obtained was filtered, washed with a mixture of methanol and ethyl acetate and then dried to get the title compound. Yield: 0.6 grams. Mehing Range: 170-172°C (purity by HPLC: 99.79%).
Example-9: Purification of metopimazine
Metopimazine (9 grams) was dissolved in methylene chloride (270 ml) and subjected to carbon treatment. The reaction mixture was filtered through hyflow and washed with methylene chloride. The filtrate was distilled off completely under reduced pressure, acetone and acetonitirle was added to the obtained residue at 25-30°C. The reaction mixture was heated to reflux and stirred the reaction mixture for 15 minutes. The reaction mixture was cooled to 5°C and stirred for an hour. The solid obtained was filtered, washed with a mixture of acetone and acetonitirle and then dried to get the title compound. Yield: 6 grams (purity by HPLC: 99.82%)

We claim:
1. 10-(3-halopropyl)-2-(methylthio)-10/f-phenothiazine compound represented by the
following structural formula

wherein X is a halogen.
2. Use of compoimds as claimed in claim 1, in the preparation of metopimazine or its pharmaceutically acceptable salts.
3. A process for the preparation of 10-(3-halopropyl)-2-(methyltiuo)-10//-phenothiazine the compounds of general formula-4,

wherein X is halogen,
which comprises of reacting the 2-(methylthio)-10/f-phenothiazine compoimd of
formula-2

with 1,3-dihalo propane compounds of general formula-3

wherem X is a halogen which may be either same or different, in presence of a suitable base selected from organic or inorganic bases or its aqueous solution in a suitable solvent selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or mixtures thereof, in presence or absence of phase

transfer catalyst to provide the 10-(3-halopropyl)-2-(methylthio)-10^-phenothiazine the compounds of general formula-4.
4. A process for the preparation of 10-(3-halopropyl)-2-(methylsulfonyl)-10//-
phenothiazine compounds of general formula-5

which comprises of oxidizing the 10-(3-halopropyl)-2-(methylthio)-10//-phenothiazine compound of general formula-4

with a suitable oxidizing agent selected from hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; in presence of catalyst like ammonium molybdate and in presence or absence of a phase transfer catalyst in a suitable solvent selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or mixtures thereof, to provide the compound of formula-5.
5. A novel process for the preparation of the metopimazine compound of formula-1
through the novel intermediate compound of formula-4, which comprises of
a) reacting the 2-(methylthio)-10//-phenothiazine compound of formula-2 with 1,3-dihalo propane compounds of general formula-3

wherein X is a halogen which may be the same or different,
in presence of a suitable base selected from organic or inorganic bases and
suitable solvent selected from alcohols, esters, hydrocarbons, chloro, polar

aprotic, nitrile, ketone or mixtures thereof provides the 10-(3-halopropyl)-2-(methylthio)-10/f-phenothiazine compounds of general formuIa-4,

b) oxidizing the compoimds of general formula-4 with a suitable oxidizing agent in
selected from hydrogen peroxide, per acids such as peracetic acid, trifluoro
peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; in
presence of catalyst like ammonium molybdate and in presence or absence of a
phase transfer catalyst in a suitable solvent selected from alcohols, esters,
hydrocarbons, chloro, polar aprotic, nitrile, ketone or mixtures thereof, to provide
the compound of formula-5,

c) reacting the compounds of general formula-5 with piperidine-4-carboxamide in
presence of suitable base selected frx}m organic or inorganic base in a suitable
solvent selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile,
ketone or mixtures thereof to provide the metopimazine compound of formula-1.
6. A novel process for the preparation of the metopimazine compound of formula-1, which comprises of
a) reacting the 2-(methylthio)-10//-phenothiazine compound of formula-2 with l-bromo-3-chloro propane compound of formula-3a in presence of aqueous sodium hydroxide and tetrabutyl ammonium bromide in toluene to provide 10-(3-chloropropyl)-2-(methylthio)-10//-phenothiazine compound of formula-4a.
b) oxidizing compound of formula-4a with hydrogen peroxide in presence ammonium molybdate and tetrabutyl ammonium bromide in chloroform to provide 10-(3-chloropropyI)-2-(methylsulfonyl)-10/f-phenothiazine compound of formula-5a.

c) reacting the compound of formula-5a with piperidine-4-carboxaniide in presence of triethyl amine in a suitable alcoholic solvents to provide the metopimazine compound of formula-1,
7. A process for the purification of metopimazine compound of formula-1 comprises of
the following steps,
a) dissolving the crude metopimazine in alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile and ketone,
b) subjecting the solution to carbon treatment,
c) filtering the solution through hyflow and washing with the corresponding solvent,
d) distilling off the solvent completely under reduced pressure,
e) suspending the residue in a mixture of solvent selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile and ketone,
f) heating the reaction mixture to reflux,
g) cooling the reaction mixture,
h) filtering the solid and washing with mixture of methanol and ethyl acetate, i) drying the solid to get the pure title compoimd.
8. Novel crystalline form of metopimazine compound of formula-1, which is characterized by its PXRD having peaks at 4.37, 8.75, 9.76, 13.16, 17.59, 19.10, 19.62, 19.92, 19.92, 21.73, 22.05, 26.05 and 31.06 ± 0.2 degrees 28 and by its differential scanning calorimetry showing endothermic peak at 173.65°C.
9. An improved process for the preparation of the metopimazine compound of formula-1, which comprises of
a) acylating the 2-(methylthio)-10//-phenothiazine compound of formula-2

with a suitable acylating agent like acetyl chloride in a suitable solvent selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or mixtures thereof, to provide the compound of formula-6, optionally

recrystallisation of compound of formula-6 from a suitable hydrocarbon solvent provides pure compound of formula-6,

b) oxidizing compound of formula-6 with oxidizing agent selected from hydrogen
peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid
and the like; in presence of a catalyst like ammonium molybdate in a suitable
solvent selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile,
ketone or mixtures thereof and in presence or absence of phase transfer catalyst
followed by hydrolysis of the obtained compound with suitable aqueous basic
solutions, provides the 2-( methylsulfonyl)-10//-phenothiazine compound of
formula-7.

c) reacting the compound of formula-7 with 1,3-dihalo compound of general
formula-3,

Wherein X is a halogen which may be the same or different,
in presence of suitable base selected from inorganic or organic base or its aqueous
solution, in a suitable solvent selected from alcohols, esters, hydrocarbon, chloro,
polar aprotic, nitrile, ketone or mixtures thereof, provides the compoimd of
formula-5,


d) reacting the compound of formula-5 with piperidine-4-carboxamide in presence of a suitable base selected from inorganic or organic bases, in a suitable solvent selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or mixtures thereof, to provide the metopimazine compound of formula-1,
e) optionally purifying the compound of formula-1 using a suitable solvents selected from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or mixtures thereof to provide the pure compound of formula-1.
10. An improved process for the preparation of the metopimazine compound of formula-1 comprises of the following steps;
a) acylating the 2-(methylthio)-10/f-phenothiazine compound of formula-2

with acetyl chloride in toluene followed by crystallisation of obtained compound in cyclohexane to provide the compound of formula-6,

b) oxidizing the compound of formula-6 with hydrogen peroxide in presence of a
ammonium molybdate and tetrabutylammoniumbromide in chloroform, followed
by hydrolysis of the obtained compound with aqueous sodium hydroxide provides
the 2-( methylsulfonyl)-10/f-phenothiazine compound of formula-7,

c) reacting the compound of formula-7 with 1,3-dibromo propane compound of
formula-Sb in presence of aqueous sodium hydroxide and

tetrabutylammoniumbromide in toluene provides the 10-(3-bromopropyl)-8-(methylsulfonyl)-10/f-phenothiazine compound of formula-5b,

d) reacting the compound of foraiula-5b with piperidine-4-carboxamide in presence
of triethylamine in isopropylalchol to provide the metopimazine compound of
formula-1,
e) optionally purifying the compound of formula-l using a suitable solvents selected
from alcohols, esters, hydrocarbons, chloro, polar aprotic, nitrile, ketone or
mixtures thereof to provide the pure compound of formula-l.