Description:FORM 2

THE PATENTS ACT,
(39 OF 1970)
THE PATENT RULES, 2003.

COMPLETE SPECIFICATION
(SECTION 10 AND RULE 13)

“A NEW IMPROVED PROCESS FOR THE PREPARATION OF CHLORO SUBSTITUTED NITRO THIOANISOLE DERIVATIVES”

PURVIEW LIFESCIENCES P LTD
3rd floor, Trendz Solitaire, Near Westin Hotel, Vittalrao Nagar, Hitech City, HYDERABAD-500 081

The following specification particularly describes the invention and the manner in which it is to be performed.
“A NEW IMPROVED PROCESS FOR THE PREPARATION OF CHLORO SUBSTITUTED NITROTHIOANISOLE DERIVATIVES”

FIELD OF THE INVENTION:
The present invention provides a new improved process for the preparation of chloro substituted nitro thioanisole derivatives of Formula (I).

Formula (I)

BACKGROUND OF THE INVENTION:

U.S. Patent No. 4298761 describes a process for the preparation of 4-nitrothioanisole starting from 4-nitrochlorobenzene by reaction with Na2S2, then with an alkaline Na2S solution followed by a methylating agent. This method involves usage of Sodium sulphide and Sulphur, which are hazardous and corrosive to eyes and skin and causes tissue damage and corneal damage on contact. The process further involves multiple operations for the preparation corresponding thioanisole derivatives which are tedious and required longer times to completion and thus increases the production cost of the product on industrial scale. Our impugned invention avoids the usage of hazardous chemicals and provides a simple and commercially scale process.
US4124646A discloses a process for Thioanisole derivatives from corresponding mercaptan derivatives by usage of methylating reagent in their gaseous phase in presence of catalysts at elevated temperatures. Usage of methylating reagents in their gaseous phase on larger scales are not safe and non-recommendable at industrial scale. The present invention avoids usage of both gaseous phase methylating reagent and expensive catalyst for the conversion and provides a simple, scalable and economically suitable process.
Based on the aforementioned drawbacks, the inventors of present invention have found an improved, commercially viable and environmentally friendly process for preparing chloro substituted nitro thioanisole derivatives with higher yields and purities to resolve the problems associated with the processes described in the prior art.

ADVANTAGES OF PRESENT INVENTION OVER PRIOR ART:
1. Synthesis of pure chloro substituted nitro thioanisole derivatives with higher purities and yields.
2. Avoid of hazardous and expensive catalysts.
3. Easily operable, reproducible and non-tedious process.
4. Suitable for large scale synthesis.

SUMMARY OF THE INVENTION:
An embodiment of the present invention is to provide a process for synthesis of chloro substituted nitro thioanisole derivatives of Formula (I), comprising the steps of:
a) reaction of compound of Formula-II with a fluorinating agent in presence of dimethyl sulfoxide to obtain compound of Formula-I;

b) optionally, purifying the compound of Formula-I obtained in step-a) using an alcoholic solvent.

The synthetic route disclosed herein results chloro substituted nitro thioanisole derivatives of Formula (I) at higher levels of purity and yields by reducing the cost, time of product cycle and also by avoiding usage of hazardous and expensive catalysts in previous synthetic methods.

DETAILED DESCRIPTION OF THE INVENTION
The present invention will be further described below in conjunction with specific embodiments. The examples are only preferred embodiments of the present invention and are not intended to limit the present invention.
In a preferred embodiment, the present invention provides a process for synthesis of chloro substituted nitro thioanisole derivatives of Formula (I), comprising the steps of:

a) reaction of compound of Formula-II with a fluorinating reagent in presence of dimethyl sulfoxide at a suitable temperature to obtain compound of Formula-I;

b) optionally, purifying the compound of Formula-I obtained in step-a) using an alcoholic solvent and activated carbon at suitable temperatures.
In aspects, conversion of compounds of Formula II to compounds of Formula I (step a) may carried out in presence of suitable fluorinating reagent in presence of dimethyl sulfoxide at a suitable temperature. Fluorinating reagents used in reaction include but not limited to potassium fluoride, sodium fluoride, cesium fluoride, elemental fluorine, chlorine monofluoride, chlorine trifluoride and like or mixture thereof. Preferably, potassium fluoride. In aspects, the reaction (step a) may be carried out at about 40 °C to about 200 °C. Preferably, reaction may be carried out at about 160 °C to about 200 °C. More specifically, reaction may be carried out at about 188°C to 190°C.
In aspects, the compound of Formula I formed in step a) was optionally purified using an alcoholic solvent and activated carbon at suitable temperatures. The suitable alcoholic solvent used includes but not limited to methanol, ethanol, propanol, isopropanol, n-butanol, tertiary butanol and like or mixture thereof. Preferably, Methanol. In aspects, the purification step (step b) may be carried out at about 40 °C to about 65 °C. Preferably, purification may be carried out at about 45 °C to about 60 °C. More specifically, purification may be carried out at about 50°C to 55°C.
The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
The present invention is further explained in the form of following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.

Brief Manufacturing process:
Example 1: Preparation of 2-chloro-4-nitrothioanisole from 1,2-dichloro-4-nitrobenzene:
To a stirred solution of 1,2-dichloro-4-nitrobenzene (50.00 gm, 0.26 mole) in dimethyl sulfoxide (DMSO) (2.56 mole) was added Potassium fluoride (KF) (predried at 200°C for 3 hrs and pulverized) (0.34 mole). The reaction mixture is slowly heated to reflux (188°C-190°C) and maintained for 20hrs. Distilled out the excess DMSO and cooled the mixture to the room temperature. Diluted the reaction mixture water and stirred for 30 min for complete dissolution of inorganic salts. Filtered the resulting reaction mixture and washed with 2 x 50 ml of DM water. Dried the compound at 50°C-60°C to obtain 2-chloro-4-nitrothioanisole.
Purification:
2-chloro-4-nitrothioanisole obtained in above was dissolved in 500 ml of methanol at 55°C and added activated carbon (3 gr.) and stirred for 30 min at 55°C. Filtered the reaction mass through celite bed and washed with hot methanol. Resulting filtrates were cooled to 10°C and stirred for 30 min. Filtered the resulting precipitate and washed with 2 x25 ml of chilled methanol and dried the compound at 50°C (18.0 gr).

Example 2: Preparation of 2-chloro-6-nitrothioanisole from 1,2-dichloro-3-nitrobenzene:
To a stirred solution of 1,2-dichloro-3-nitrobenzene (50.00 gm, 0.26 mole) in dimethyl sulfoxide (DMSO) (2.56 mole) was added Potassium fluoride (KF) (predried at 200°C for 3 hrs and pulverized) (0.34 mole). The reaction mixture is slowly heated to reflux (188°C-190°C) and maintained for 18 hrs. Distilled out the excess DMSO and cooled the mixture to the room temperature. Diluted the reaction mixture water and stirred for 30 min for complete dissolution of inorganic salts. Filtered the resulting reaction mixture and washed with 2 x 50 ml of DM water. Dried the compound at 50°C-60°C to obtain 2-chloro-6-nitrothioanisole.
Purification:
2-chloro-6-nitrothioanisole obtained in above was dissolved in 500 ml of methanol at 55°C and added activated carbon (3 gr.) and stirred for 30 min at 55°C. Filtered the reaction mass through celite bed and washed with hot methanol. Resulting filtrates were cooled to 10°C and stirred for 30 min. Filtered the resulting precipitate and washed with 2 x25 ml of chilled methanol and dried the compound at 50°C (18.3 gr).

Example 3: Preparation of 4-chloro-2-nitrothioanisole from 1,4-dichloro-2-nitrobenzene:
To a stirred solution of 1,4-dichloro-2-nitrobenzene (50.00 gm, 0.26 mole) in dimethyl sulfoxide (DMSO) (2.56 mole) was added Potassium fluoride (KF) (predried at 200°C for 3 hrs and pulverized) (0.34 mole). The reaction mixture is slowly heated to reflux (188°C-190°C) and maintained for 18 hrs. Distilled out the excess DMSO and cooled the mixture to the room temperature. Diluted the reaction mixture water and stirred for 30 min for complete dissolution of inorganic salts. Filtered the resulting reaction mixture and washed with 2 x 50 ml of DM water. Dried the compound at 50°C-60°C to obtain 4-chloro-2-nitrothioanisole.
Purification:
4-chloro-2-nitrothioanisole obtained in above was dissolved in 500 ml of methanol at 55°C and added activated carbon (3 gr.) and stirred for 30 min at 55°C. Filtered the reaction mass through celite bed and washed with hot methanol. Resulting filtrates were cooled to 10°C and stirred for 30 min. Filtered the resulting precipitate and washed with 2 x25 ml of chilled methanol and dried the compound at 50°C (17.9 gr).

Example 4: Preparation of 3-chloro-5-nitrothioanisole from 1,3-dichloro-5-nitrobenzene:
To a stirred solution of 1,3-dichloro-5-nitrobenzene (50.00 gm, 0.26 mole) in dimethyl sulfoxide (DMSO) (2.56 mole) was added Potassium fluoride (KF) (predried at 200°C for 3 hrs and pulverized) (0.34 mole). The reaction mixture is slowly heated to reflux (188°C-190°C) and maintained for 18 hrs. Distilled out the excess DMSO and cooled the mixture to the room temperature. Diluted the reaction mixture water and stirred for 30 min for complete dissolution of inorganic salts. Filtered the resulting reaction mixture and washed with 2 x 50 ml of DM water. Dried the compound at 50°C-60°C to obtain 3-chloro-5-nitrothioanisole.
Purification:
3-chloro-5-nitrothioanisole obtained in above was dissolved in 500 ml of methanol at 55°C and added activated carbon (3 gr.) and stirred for 30 min at 55°C. Filtered the reaction mass through celite bed and washed with hot methanol. Resulting filtrates were cooled to 10°C and stirred for 30 min. Filtered the resulting precipitate and washed with 2 x25 ml of chilled methanol and dried the compound at 50°C (18.3 gr).
Without wishing to be bound to a theory, the process described in the present invention is believed to be an improved process for the preparation of chloro substituted nitro thio-anisole derivatives of Formula (I) or pharmaceutical acceptable salts and purification process thereof which is stable, economical, and commercially scalable.
The process described in the present invention also discloses the improved process for the preparation of chloro substituted nitro thio-anisole derivatives of Formula (I), or pharmaceutical acceptable salts and purification process thereof which is stable, economical, and commercially scalable, results in higher yields in a short run time.
While the illustrative embodiments of the invention have been described with particularity, it will be understood that various other modifications will be apparent to and can be readily made by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is not intended that the scope of the claims appended hereto be limited to the examples and descriptions set forth hereinabove but rather that the claims be construed as encompassing all the features of patentable novelty which reside in the present invention, including all features which would be treated as equivalents thereof by those skilled in the art to which the invention pertains.

Dated this 17th Day of March 2024
, Claims:I/ We Claim:
1. A new improved process for preparation of chloro substituted nitrothioanisole derivatives of Formula I,

Comprising;
a) reaction of compound of Formula II with a fluorinating reagent in presence of dimethyl sulfoxide (DMSO) to obtain compound of Formula I;

b) optionally, purifying the compound of Formula I obtained in step a) using an alcoholic solvent.
2. The process as claimed in claim 1, wherein the fluorinating reagent used in step a) is Potassium fluoride (KF).
3. The process as claimed in claim 1, wherein an alcoholic solvent used in step b) is methanol.

Dated this 17th Day of March 2024