Description:FORM 2

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

COMPLETE SPECIFICATION
(SECTION 10 AND RULE 13)

A NEW PROCESS FOR SYNTHESIS OF 4-HALOPHENYL METHYL SULFONE 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 PROCESS FOR SYNTHESIS OF 4-HALOPHENYL METHYL SULFONE DERIVATIVES
FIELD OF THE INVENTION:
The present invention relates to a new process for synthesis of 4-halophenyl methyl sulfone derivatives of Formula (I).

Formula (I)
BACKGROUND OF THE INVENTION:

Phenyl methyl sulfone derivatives are a class of acaricidal drugs, which are effective against adult mites and mite eggs and can control various mites in cotton, fruit, vegetable and other crops.
CN1651408 discloses a process for preparation of 4-bromophenyl methyl sulfone by the reaction of 4-bromo iodo benzene with sodium methanesulfinate in presence of copper iodide and L-sodium proline salt. This method produces dimer impurities with a lower yields and required multiple purifications of final product which increases the production cost and is not suitable for industrial production. Our impugned invention avoids the formation of dimer impurities and provides a simple and commercially scalable process.
JP2011079766 discloses a process for preparation of 4-halophenyl alkyl sulfones starting from Thioanisole in two steps. First step involves halogenation of Thioanisole in presence of Lewis acid. This step produces ortho isomers which are difficult to purify and results lower yields and purities. Second step involves the oxidation using expensive Tungsten reagents such as Sodium tungstate dihydrate which further increases the overall cost of the final product. The present invention avoids both formation of ortho isomers and usage of expensive reagents 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 4-halophenyl methyl sulfones with higher yields and purities to resolve the problems associated with the processes described in the prior art.

Advantages of the present invention over the prior arts:
1. Synthesis of pure 4-halophenyl alkyl sulfones with higher purities and yields.
2. Avoid the formation of dimer and ortho isomer impurities,
3. Avoid of toxic and expensive catalysts,
4. Easily operable, reproducible, and non-tedious process.
5. Suitable for large scale synthesis.

SUMMARY OF THE INVENTION:
An embodiment of the present invention is to provide a process for synthesis of 4-halophenyl methyl sulfone derivatives of Formula (I), comprising the steps of:
a) conversion of 4-acetamidobenzenesulfonyl chloride into N-[4-(methylsulfonyl) phenyl] acetamide,
b) hydrolysis of N-[4-(methylsulfonyl) phenyl] acetamide obtained in step (a) into 4-(methylsulfonyl) aniline,
c) conversion of 4-(methylsulfonyl) aniline obtained in step (b) into 4-halophenyl methyl sulfone derivatives.
The synthetic route disclosed herein results 4-halophenyl methyl sulfone derivatives at higher levels of purity and yields by reducing the cost, time of product cycle and by eliminating formation of dimer and ortho impurities formed in previous synthetic methods.
Another embodiment of the present invention relates to a process for the preparation of 4-halophenyl methyl sulfone derivatives which is stable, scalable and commercially viable in reproducing higher yields in higher quantities.

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 4-halophenyl methyl sulfone derivatives of Formula (I), comprising the steps of:

a) reaction of 4-acetamidobenzenesulfonyl chloride with Sodium sulfite in presence of suitable base and solvent to form N-[4-(methylsulfonyl)phenyl]acetamide,

b) hydrolysis of N-[4-(methylsulfonyl)phenyl]acetamide obtained in step (a) into 4-(methylsulfonyl) aniline in presence of a suitable base,

c) conversion of 4-(methylsulfonyl) aniline obtained in step (b) into 4-halophenyl methyl sulfone derivatives in presence of suitable reagents and solvent.

In aspects, conversion of 4-acetamidobenzenesulfonyl chloride into N-[4-(methylsulfonyl) phenyl]acetamide (step a) may carried out in presence of Sodium sulfite and dimethyl sulfate using a suitable base and solvent. Bases used in reaction include but not limited to alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, triethyl amine, diisopropyl amine, diisopropyl ethylamine, ammonia, ammonium hydroxide and like or mixture thereof. Preferably, alkali metal bicarbonates. More preferably, sodium bicarbonate. The solvents used include but not limited to methanol, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, THF, DMF, DMAc, water and like or a mixture thereof. Specifically, the solvent may be water.
In aspects, conversion of N-[4-(methylsulfonyl)phenyl]acetamide into 4-(methylsulfonyl) aniline (step b) may carried out in presence of a suitable alkaline solution. The suitable alkaline solution includes but not limited to sodium hydroxide, potassium hydroxide and like or a mixture thereof. Specifically, sodium hydroxide solution. More specifically, 10% sodium hydroxide solution.
In aspects, conversion of 4-(methylsulfonyl) aniline into 4-halophenyl methyl sulfone (step c) may carried out in presence of sulfuric acid, a suitable metal nitrite and copper halides. Metal nitrites used in the reaction include but not limited to sodium nitrite, potassium nitrite and like or a mixture thereof. Preferably, sodium nitrite. Copper halide used in reaction include but not limited to copper bromide and copper iodide.
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:
Conversion of 4-acetamidobenzenesulfonyl chloride into N-[4-(methylsulfonyl) phenyl] acetamide (Step a):

To a stirred solution of NaHCO3 (1.02 kg) in water (3.5 lit) was added NaSO3 (770 g) at room temperature. Heated the reaction mass to 70 °C to 75 °C and maintained for one hour. Added 4-acetamidobenzenesulfonyl chloride (700 g) slowly (basic pH of the reaction mixture was maintained) to the above reaction mass at 80 °C and stirred for 2 hours. Cooled the reaction mass to 50 °C to 55 °C and added dimethyl sulfate (945 g). Stirred the reaction mass at 50 °C to 55 °C for 2 hours. Heated the resulting reaction mass further to 90 °C to 95 °C and maintained for 4 hours. Cooled the reaction mass to 20 °C. Filtered the resulting precipitate and washed with water to obtain desired product (436.5 g).

Conversion of N-[4-(methylsulfonyl) phenyl] acetamide into 4-(methylsulfonyl) aniline (Step b):

To a stirred 10% lye solution (4.5 lit) was added N-[4-(methylsulfonyl) phenyl] acetamide (1.1 kg) at room temperature. Heated the reaction mass to 90 °C to 95 °C and stirred for 2 hours. On completion of reaction, cooled the reaction mass to 20 °C. Filtered the resulting precipitate and dried under vacuum to obtain desired product (688.0 g).

Conversion of 4-(methylsulfonyl) aniline into 4-bromophenyl methyl sulfone (Step c):
To a stirred solution of 4-(methylsulfonyl) aniline (500.0 g) in water (1.3 lit) was added H2SO4 (500.0 mL) at room temperature. Cooled the reaction mass to 0 °C and added a solution NaNO2 (prepared by dissolving 230 g of NaNO2 in 400 mL of water). Stirred the resulting reaction mixture at 0 °C to 5°C for 45 minutes. Added the resulting solution to a solution of Copper bromide (400.0 g) and 48% HBr (937.5 mL) at 50 °C to 55 °C and stirred for 2 hours. On completion of reaction, quenched the reaction mass by pouring slowly into ice cold water. Filtered the resulting precipitate and washed with water to obtain desired product.
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 4-halophenyl methyl sulfone derivatives 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 process for the preparation of 4-halophenyl methyl sulfone derivatives 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 day of 1st June 2023
, Claims:We Claim:
1. A process for preparation of 4-halophenyl methyl sulfone derivatives of Formula (I),

Formula (I)
Comprising;
a) reacting 4-acetamidobenzenesulfonyl chloride with Sodium sulfite and dimethyl sulfate in presence of suitable base to obtain N-[4-(methylsulfonyl)phenyl] acetamide,

b) hydrolysis of N-[4-(methylsulfonyl)phenyl]acetamide obtained in step (a) into 4-(methylsulfonyl) aniline in presence of a suitable base,

c) reacting 4-(Methylsulfonyl)aniline obtained in step (b) with sodium nitrite and sulphuric acid in presence of suitable reagent to obtain 4-halophenyl methyl sulfone derivatives of Formula (I).

2. The process as claimed in claim 1, wherein the suitable base used in step (a) is sodium bicarbonate.
3. The process as claimed in claim 1, wherein the suitable base used in step (b) is an alkaline solution.
4. The process as claimed in claim 3, wherein the alkaline solution used in step (b) is 10% lye solution.
5. The process as claimed in claim 1, wherein the suitable reagent used in step (c) is copper halide having Formula “CuX” (where X is -Cl or -Br).

Dated this Day 1st of June 2023

Signature:
Dr. VURE PRASAD
Patent Agent Reg. No.: IN/PA-1636