F0RM2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
A process for the preparation of 2-Methyl sulphonyl phenothiazin
2. APPLICANT (S)
(a) NAME: Centaur Pharmaceuticals Pvt Ltd
(b) NATIONALITY:
An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:
Centaur Pharmaceuticals Pvt Ltd, Centaur House, Near Grand Hyatt, Vakola, Santacruz (East), Mumbai, Maharashtra India Pin Code: 400055.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 2-Methyl sulphonyl phenothiazine compound of structural formula (I) which is an intermediate of Metopimazine compound of structural formula (II).

BACKGROUND OF THE INVENTION
Metopimazine is an antiemetic and is chemically defined as l-[3-[2-(Methylsulfonyl)-10H-phenothiazin-10-yl]propyl]-4-piperidinecarboxamide. Metopimazine has been marketed under the brand name Vogalene in France. It is indicated for the prevention and treatment of nausea and vomiting. Metopimazine can be depicted by compound of structural formula (II).

Metopimazine is known from German patent No. 1092476. German patent No. 1092476 provides a process for the preparation of Metopimazine, which is depicted in scheme-I as given below:


The disclosed process involves the reaction of methyl thioether compound of structural formula (III) with sodium amide followed by acetic anhydride to provide an amide compound of structural formula (IV), which on oxidation with peracid followed by treatment with sodium hydroxide affords the phenothiazine compound of structural formula (V). The said compound of structural formula (V) on reaction with 3-chloro-l-bromo-propane provides compound of structural formula (VI), which on condensation with piperidine-4-carboxamide provides Metopimazine compound of structural formula (II).

The process of German patent No. 1092476 is disadvantageous as it involves use of very strong base such as NaNH2 which is difficult to handle in a large scale process and which leads to formation of by-products. In the acetylation process acetic anhydride is used which is difficult to procure commercially. Oxidation involves use of meta-chloroperbenzoic acid which produces meta-chlorobenzoic acid as a byproduct which is not easily removed. Hence the process is not environment friendly and commercially viable.
In view of the above the inventors of present invention have designed an efficient, more economical, less hazardous and eco-friendly process for the preparation of 2-Methyl sulphonyl phenothiazine compound of structural formula (I) which is intermediate of Metopimazine compound of structural formula (II).
2-Methyl sulphonyl phenothiazine compound of structural formula (I) can be converted to Metopimazine compound of structural formula (II) by method disclosed in German patent No. 1092476 by reaction of 2-Methyl sulphonyl phenothiazine compound of structural formula (I) with l-bromo-3-chloropropane to give 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine, which on condensation with piperidine-4-carboxamide provides Metopimazine compound of structural formula (II).
OBJECT OF THE INVENTION
The first object of the present invention to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of 2-Methyl sulphonyl phenothiazine compound of structural formula (I) which is intermediate of Metopimazine compound of structural formula (II).


Another object of the present invention is provide a simple, cost efficient and environment friendly process for preparation of Metopimazine compound of structural formula (II).
SUMMARY OF THE INVENTION
A first aspect of present invention is to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of 2-Methyl sulphonyl phenothiazine compound of structural formula (I) comprising:
i. reacting 10H-phenothiazine compound of structural formula (VII) with ethyl
chloroformate in an organic solvent in the presence of base to obtain
compound of structural formula (VIII)

ii. reacting compound of structural formula (VIII) with chlorosulphonic acid to obtain compound of structural formula (IX)

iii. reacting compound of structural formula (IX) with thionyl chloride to obtain compound of structural formula (X) which is in-situ reacted with sodium bicarbonate, sodium sulfite to obtain compound of structural formula (XI)

bicarbonate, sodium sulfite to obtain compound of structural formula (XI) which further in-situ reacted with an methylating agent to obtain compound of structural formula (XII)

iv. reacting compound of structural formula (XII) with an alkali metal hydroxide
in alcohol to obtain compound of structural formula (I)

The second aspect of the present invention is to provide a process for the preparation of 2-Methyl sulphonyl phenothiazine compound of structural formula (I) comprising: i. reacting 10H-Phenothiazine compound of structural formula (VII) with ethyl chloroformate in dimethyl formamide solvent in the presence of sodium


ii. reacting compound of structural formula (VIII) with chlorosulphonic acid to obtain compound of structural formula (IX)

iii. reacting compound of structural formula (IX) with thionyl chloride to obtain compound of structural formula (X) which is in-situ reacted with sodium bicarbonate and sodium sulfite to obtain compound of structural formula (XI) which further in-situ reacted with methyl iodide to obtain compound of structural formula (XII)


iv. reacting compound of structural formula (XII) with an alkali metal hydroxide in alcohol to obtain compound of structural formula (I)

The third aspect of the present invention is to provide a process for the preparation of
2-Methyl sulphonyl phenothiazine compound of structural formula (I) comprising:
i. reacting 10H-Phenothiazine compound of structural formula (VII) with Ethyl
chloroformate in dimethyl formamide solvent in the presence of sodium
hydride and 4-Dimethylaminopyridine (DMAP) as base to obtain compound
of structural formula (VIII)

ii. reacting compound of structural formula (VIII) with chlorosulphonic acid to obtain compound of structural formula (IX)

iii. reacting compound of structural formula (IX) with thionyl chloride to obtain compound of structural formula (X) which is in-situ reacted with sodium

bicarbonate and sodium sulfite to obtain compound of structural formula (XI) which further in-situ reacted with methyl iodide to obtain compound of structural formula (XII)

iv. reacting compound of structural formula (XII) with an alkali metal hydroxide selected from the group comprising of sodium hydroxide., potassium hydroxide or lithium hydroxide in alcohol to obtain compound of structural formula (I)

DETAILED DESCRIPTION OF INVENTION:
10H-Phenothiazine compound of structural formula (VII) is available commercially,

10H-Phenothiazine compound of structural formula (VII) is reacted with Ethyl chloroformate in organic solvent and presence of base at a temperature in the range of 0°C to 100°C for the period of 1 hour to 5 hours to obtain compound of structural formula (VIII).
The organic solvent is polar aprotic solvent selected from the group consisting of dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, N-methylpyrrolidone or mixture(s) thereof.
The base is one or more selected from the group consisting of sodium hydride, vitride, Dimethylaminopyridine (DMAP) or pyridine.
Compound of structural formula (VIII) is reacted with chlorosulphonic acid in a chlorinated solvent at a temperature in the range of 0°C to 100°C for the period of 1 hour to 5 hours to obtain compound of structural formula (IX)
The chlorinated solvent is selected from the group consisting of dichloromethane, dichloroethane, chloroform or mixture(s) thereof
Compound of structural formula (IX) is reacted with thionyl chloride in toluene at a
temperature in the range of 20°C to 110°C for the period of 1 hour to 5 hours to
obtain compound of structural formula (X) which is in-situ reacted with sodium
bicarbonate, sodium sulfite to obtain compound of structural formula (XI) which
further in-situ reacted with methylating agent to obtain compound of structural
formula (XII)
Methylating agent is selected from the group consisting of methyl iodide, methyl bromide, methyl chloride and dimethyl sulfate.

Compound of structural formula (XII) is reacted with alkali metal hydroxide in alcohol solvent at a temperature in the range of 20°C to 120°C for the period of 1 hour to 5 hours to obtain compound of structural formula (I).
Alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide.
Alcohol solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol or mixture(s) thereof.
The compound of structural formula (I) was isolated by means of filtration, recrystallization in alcohol solvent selected from the group consisting of methanol, ethanol, propanol or mixture thereof and drying in oven at 60°C.
The 2-Methyl sulphonyl phenothiazine compound of structural formula (I) is converted in to Metopimazine compound of structural formula (II) by method known in the art.
EXAMPLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of Ethyl-10H-phenothiazine-10-carboxylate
To a solution of 10H-Phenothiazine 10 g was dissolved in dimethyl formamide 40 mL was added Sodium hydride (60%) 2.9 g, 4-Dimethylaminopyridine (DMAP) 1.2 g and Ethyl chloroformate 9.1 g. Reaction mixture was stirred at 20°C to 40°C for 3 hours. Acetic acid 2.0 mL was added in the reaction mixture. Water 40 mL was added and stirred. Solid was filtered, washed with water and dried in oven at 60°C. Yield=13g(95.3%).

HPLC Purity= 99.54 %.
Example 2: Preparation of 10-(Ethoxycarbonyl)-10H-phenothiazine-2-suIfonic acid
To a solution of Ethyl- 10H-phenothiazine-10-carboxylate 12 g in dichloromethane 60
mL was added Chlorosulfonic acid 10.3 g. Reaction mixture was stirred at 20°C to
40°C for 6 hours. Reaction mixture was quenched in water 145 mL. The organic layer
was separated and sodium chloride 40 g was added in aqueous layer. Solid was
precipitated out, filtered, and dried in oven at 60°C.
Yield= 14.7 g (94.8%). HPLC Purity= 99.30 %.
Example 3: Preparation of Ethyl-(2-methyl sulphonyl)-10H-phenothiazine-10-carboxylate
To a solution of 10-(Ethoxycarbonyl)-10H-phenothiazine-2-sulfonic acid 10 g in toluene 90 mL was added thionyl chloride 13.0 g and refluxed at 110°C for 3-5 hours. Reaction mass was quenched in water 60 mL. The organic layer and aqueous layer were separated. The organic layer was added in the solution of sodium bicarbonate 14.4 g and sodium sulfite 7.0 g in water 80 mL. Reaction mass was stirred at 20°C to 50°C for 4 hours. Reaction mixture was cooled and organic layer were separated. Methyl iodide 11.8 g was added in aqueous layer. Reaction mass was stirred at 20°C to 50°C for 4 hours. The solid was filtered, washed with water and dried in oven at 60°C. Ethyl-(2-methyl sulphonyl)-10H-phenothiazine-10-carboxylate crude was crystallized in methanol. Yield= 10.8 g (90.3%). HPLC Purity= 99.72 %.

Example 4: Preparation of 2-methyl sulphonyl phenothiazine
To a solution of Ethyl-(2-methyl sulphonyl)-10H-phenothiazine-10-carboxylate 6.0 g
in methanol 30 mL was added Potassium hydroxide 1.2 g and heated to 60-65°C for 4
hours. Cool the reaction mixture to 10°C. Solid was filtered, washed with methaqpl
and dried.
Yield= 4.5 g (94.6%).
HPLC Purity= 99.95 %.

We claim:
1. A Process for the preparation of 2-Methyl sulphonyl phenothiazine compound of structural formula (I) comprising: i. reacting 10H-Phenothiazine compound of structural formula (VII) with ethyl
chloroformate in organic solvent and presence of base to obtain compound-of
structural formula (VIII)

ii. reacting compound of structural formula (VIII) with chlorosulphonic acid in organic solvent to obtain compound of structural formula (IX)

iii. reacting compound of structural formula (IX) with thionyl chloride in an organic solvent to obtain compound of structural formula (X) which is in-situ reacted with sodium bicarbonate and sodium sulfite to obtain compound of structural formula (XI) which further in-situ reacted with methylating agent to obtain compound of structural formula (XII)


iv. reacting compound of structural formula (XII) with alkali metal hydroxide in alcohol to obtain compound of structural formula (I)

2. The process as claimed in claim l(i) wherein organic solvent is polar aprotic solvent,
3. The process as claimed in claim 2 wherein polar aprotic solvent selected from the group consisting of dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, N-methylpyrrolidone or mixture(s) thereof.

4. The process as claimed in claim l(i) wherein base is one or more selected from the
group consisting of sodium hydride, vitride, Dimethylaminopyridine (DMAP) or
pyridine.
5. The process as claimed in claim l(ii) wherein organic solvent is chlorinated solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform or mixture(s) thereof.
6. The process as claimed in claim l(iii) wherein organic solvent is toluene.
7. The process as claimed in claim l(iii) wherein methylating agent is selected from the group consisting of methyl iodide, methyl bromide, methyl chloride and dimethyl sulfate.
8. The process as claimed in claim l(iv) wherein alkali metal hydroxide is selected
from sodium hydroxide, potassium hydroxide or lithium hydroxide.
9. The process as claimed in claim l(iv) wherein alcohol solvent is selected from the
group consisting of methanol, ethanol, propanol, isopropanol, butanol or mixture(s)
thereof.
10. The process as claimed in claim l(iv) wherein 2-Methyl sulphonyl phenothiazine
compound of structural formula (I) is recrystallized in alcohol solvent selected from
the group consisting of methanol, ethanol, propanol or mixture thereof.