DESC:FIELD
The present disclosure relates to a process for the preparation of 2-(2,2-Difluoroethoxy)-6-(trifluoromethyl) benzenesulfonyl chloride.
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
Penoxsulam is a post-emergence systemic herbicide used on rice crops for the control of broad-leaf weeds, aquatic weeds, and certain grasses. Penoxsulam is mainly absorbed by leaves and secondarily by roots, preventing the plants from producing a necessary enzyme - acetolactate synthase (ALS).
2-(2,2-Difluoroethoxy)-6-(trifluoromethyl) benzenesulfonyl chloride is an important intermediate used in the production of Penoxsulam. The structural representation of 2-(2, 2-difluoroethoxy)-6-(trifluoromethyl) benzenesulfonyl chloride is given as formula (I) below:

(I)
Conventional methods for the preparation of 2-(2,2-Difluoroethoxy)-6-(trifluoromethyl) benzenesulfonyl chloride are associated with drawbacks such as impurities in the final product thereby require further purification which is not economical. The impurities in the final product may affect the reactivity, efficacy, safety, and stability of the final formulation. The yield/productivity of 2-(2,2-difluoroethoxy)-6-(trifluoromethyl) benzenesulfonyl chloride obtained from the known processes is low.
Therefore, there is felt a need to provide a process for the preparation of 2-(2,2-difluoroethoxy)-6-(trifluoromethyl) benzenesulfonyl chloride that mitigates the aforestated drawbacks or at least provide an alternative solution.
OBJECTS
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:
It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
Another object of the present disclosure is to provide a process for the preparation of 2-(2,2-difluoroethoxy)-6-(trifluoromethyl) benzenesulfonyl chloride.
Yet another object of the present disclosure is to provide a process for the preparation of 2-(2,2-difluoroethoxy)-6-(trifluoromethyl) benzenesulfonyl chloride with a comparatively better purity and yield.
Still another object of the present disclosure is to provide a simple and cost-effective process for the preparation of 2-(2, 2-difluoroethoxy)-6-(trifluoromethyl) benzene- sulfonyl chloride.
Another object of the present disclosure is to provide an environment-friendly and commercially scalable process for the preparation of 2-(2,2-difluoroethoxy)-6-(trifluoromethyl) benzenesulfonyl chloride.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY
The present disclosure relates to a process for the preparation of 2-(2, 2-difluoroethoxy)-6-(trifluoromethyl) benzenesulfonyl chloride. The process comprises o-aminobenzotrifluoride is reacted with hydroxylamine salt and chloral hydrate in a first fluid medium by using a alkali metal salt and a first acid at a first predetermined temperature for a first predetermined time period to obtain a first product mixture comprising o-trifluoromethyl-isonitroso acetanilide and o-trifluoromethyl-isonitroso acetanilide is separated from the first product mixture. o-trifluoromethyl-isonitrosoacetanilide is cyclized by using a second acid in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain a second product mixture comprising 7-trifluoromethylisatin and 7-trifluoromethylisatin is separated from the second product mixture. 7-trifluoromethylisatin is oxidized by using a first oxidizing agent in a third fluid medium at a third predetermined temperature for a third predetermined time period to obtain a third product mixture comprising 2-amino-3-trifluoromethylbenzoic acid and 2-amino-3-trifluoromethylbenzoic acid is separated from the third product mixture. 2-amino-3-trifluoromethylbenzoic acid is diazotized by using a first diazotizing agent in a fourth fluid medium at a fourth predetermined temperature for a fourth predetermined time period followed by halogenating by using a halogenating agent at a fifth predetermined temperature for a fifth predetermined time period to obtain a fourth product mixture comprising 2-bromo-3-trifluoromethylbenzoic acid and 2-bromo-3-trifluoromethylbenzoic acid is separated from the fourth product mixture. 2-bromo-3-trifluoromethylbenzoic acid is chlorinated by using a first chlorinating agent in a fifth fluid medium in the presence of a catalyst at a sixth predetermined temperature for a sixth predetermined time period followed by amidating by using ammonia at a seventh predetermined temperature for a seventh predetermined time period to obtain a fifth product mixture comprising 2-bromo-3-trifluoromethylbenzamide and 2-bromo-3-trifluoromethylbenzamide is separated from the fifth product mixture. 2-bromo-3-trifluoromethylbenzamide is oxidized by using a second oxidizing agent in a sixth fluid medium at an eighth predetermined temperature for an eighth predetermined time period to obtain a sixth product mixture comprising 2-bromo-3-trifluoromethyl aniline and 2-bromo-3-trifluoromethyl aniline is separated from the sixth product mixture.
2-bromo-3-trifluoromethyl aniline is diazotized by using a second diazotizing agent at a ninth predetermined temperature for a ninth predetermined time period followed by hydrolysis in a seventh fluid medium at a tenth predetermined temperature for a tenth predetermined time period to obtain 2-bromo -3-trifluoromethyl phenol. 2-bromo-3-trifluoromethyl phenol is condensed with 2,2-difluroethyl methanesulfonate by using a base in an eighth fluid medium at an eleventh predetermined temperature for an eleventh predetermined time period to obtain a seventh product mixture comprising 2-bromo-1-(2,2-difluoroethoxy)-3-(trifluoromethyl)benzene and 2-bromo-1-(2,2-difluoroethoxy)-3-(trifluoromethyl)benzene is separated from the seventh product mixture. 2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl)benzene is reacted with a salt of ethyl mercaptan in a ninth fluid medium at a twelfth predetermined temperature for a twelfth predetermined time period to obtain an eighth product mixture comprising 2-ethylthio-3-(2,2-difluoroethoxy)benzotrifluoride and 2-ethylthio-3-(2,2-difluoroethoxy)benzotrifluoride is separated from the eighth product mixture. Oxidative chlorination of 2-(2,2,difluoroethoxy)-6-(trifluoromethyl)phenyl)(ethyl)sulfane by using a oxidative chlorinating agent at a thirteenth predetermined temperature for a thirteenth predetermined time period to obtain a ninth product mixture comprising 2-(2,2-difluoroethoxy)-6-(Trifluoromethyl)benzene sulfonyl chloride and 2-(2,2-difluoroethoxy)-6-(Trifluoromethyl)benzene sulfonyl chloride is separated from the ninth product mixture.
The hydroxylamine salt is selected from the group consisting of hydroxylamine sulphate and hydroxylamine hydrochloride.
The first fluid medium is water.
The alkali metal salt is selected from the group consisting of sodium sulphate and potassium sulphate.
The first acid is selected from the group consisting of hydrochloric acid and sulfuric acid.
The first predetermined temperature is in the range of 70°C to 100°C and the first predetermined time period is in the range of 3 hours to 5 hours.
The second acid is selected from the group consisting of sulphuric acid, methane sulfonic acid, trifluoroacetic acid and triflic acid.
The second fluid medium is selected from the group consisting of ethylene dichloride, methylene dichloride and chlorobenzene.
The second predetermined temperature is in the range of 40 °C to 60 °C.
The second predetermined time period is in the range of 3 hours to 10 hours.
The first oxidizing agent is hydrogen peroxide.
The third fluid medium is water.
The third predetermined temperature is in the range of 10 °C to 30 °C.
The third predetermined time period is in the range of 4 hours to 15 hours.
The first diazotizing agent is selected from the group consisting of a mixture of sodium nitrite and hydrobromic acid and a mixture of potassium nitrite and hydrobromic acid.
The fourth fluid medium is selected from the group consisting of water.
The halogenating agent is CuBr.
The fourth predetermined temperature is in the range of 20 °C to 40°C.
The fourth predetermined time period is in the range of 0.5 hours to 3 hours.
The fifth predetermined temperature is in the range of 20 °C to 40°C.
The fifth predetermined time period is in the range of 5 hours to 15 hours.
The first chlorinating agent is selected from the group consisting of thionyl chloride and oxalyl chloride.
The fifth fluid medium is selected from the group consisting of toluene, benzene and mono chloro benzene.
The catalyst is selected from the group consisting of dimethyl formamide and pyridine.
The sixth predetermined temperature is in the range of 50 °C to 90°C.
The sixth predetermined time period is in the range of 2 hours to 8 hours.
The seventh predetermined temperature is in the range of 5 °C to 20 °C.
The seventh predetermined time period is in the range of 0.5 hours to 5 hours.
The second oxidizing agent is selected from the group consisting of potassium hydroxide and bromine, sodium hydroxide and bromine and sodium hydroxide and chlorine and potassium hydroxide and chlorine.
The sixth fluid medium is water.
The eighth predetermined temperature is in the range of 0 °C to 100 °C.
The eighth predetermined time period is in the range of 1 hour to 3 hours.
The second diazotizing agent is sodium nitrite and sulphuric acid.
The hydrolysis is carried out using is sulfuric acid and copper sulphate.
The seventh fluid medium is water.
The ninth predetermined temperature is in the range of -2 °C to 10 °C.
The ninth predetermined time period is in the range of 30 minutes to 60 minutes.
The tenth predetermined temperature is in the range of 120 °C to 150 °C.
The tenth predetermined time period is in the range of 2 hours to 6 hours.
The second base is selected from the group consisting of potassium carbonate and sodium carbonate.
The eighth fluid medium is selected from the group consisting of dimethylformamide and N, N-dimethylacetamide.
The eleventh predetermined temperature is in the range of 100 °C to 130°C.
The eleventh predetermined time period is in the range of 1 hour to 6 hours.
The salt of ethyl mercaptan is selected from the group consisting of sodium salt of ethyl mercaptan, potassium salt of ethyl mercaptan and lithium salt of ethyl mercaptan.
The ninth fluid medium is selected from the group consisting of dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, and dimethyl sulfoxide.
The twelfth predetermined temperature is in the range of 70 °C to 90°C.
The twelfth predetermined time period is in the range of 5 hours to 8 hours.
The oxidative chlorinating agent is selected from the group consisting of acetic acid and chlorine, formic acid and chlorine and monochloroacetic acid mother liquor acetic acid and chlorine.
The thirteenth predetermined temperature is in the range of 30 °C to 50°C.
The thirteenth predetermined time period is in the range of0.5 hours to 3 hours.
The weight ratio of 2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl) benzene and salt of ethyl mercaptan is in the range of 2:1 to 4:1.
2-bromo-1-(2,2-difluoroethoxy)-3-(trifluoromethyl) benzene has the following structure

DETAILED DESCRIPTION
The present disclosure relates to a process for the preparation of 2-(2, 2-difluoroethoxy)-6-(trifluoromethyl) benzene sulfonyl chloride.
Embodiments, of the present disclosure, will now be described herein. Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.
As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed elements.
The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer, or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.
Conventional methods for the preparation of 2-(2, 2-difluoroethoxy)-6-(trifluoromethyl) benzene sulfonyl chloride are associated with drawbacks such as impurities in the final product thereby require further purification which is not economical. The impurities in the final product may affect the reactivity, efficacy, safety, and stability of the final formulation. The yield/productivity of 2-(2, 2-difluoroethoxy)-6-(trifluoromethyl) benzene sulfonyl chloride obtained from the known processes is low.
The present disclosure provides an improved process for the preparation of 2-(2, 2-difluoroethoxy)-6-(trifluoromethyl) benzene sulfonyl chloride.
The process of the present disclosure is simple, environment friendly and economical and results in improved yield and purity of 2-(2, 2-difluoroethoxy)-6-(trifluoromethyl) benzene sulfonyl chloride.
The process for the preparation of 2-(2, 2-difluoroethoxy)-6-(trifluoromethyl) benzene sulfonyl chloride comprises the steps of:
i. reacting o-aminobenzotrifluoride with hydroxylamine salt and chloral hydrate in a first fluid medium by using a alkali metal salt and a first acid at a first predetermined temperature for a first predetermined time period to obtain a first product mixture comprising o-trifluoromethyl-isonitroso acetanilide and separating o-trifluoromethyl-isonitrosoacetanilide from the first product mixture;
ii. cyclizing o-trifluoromethyl-isonitrosoacetanilide by using a second acid in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain a second product mixture comprising 7-trifluoromethylisatin and separating 7-trifluoromethylisatin from the second product mixture;
iii. oxidizing 7-trifluoromethylisatin by using a first oxidizing agent in a third fluid medium at a third predetermined temperature for a third predetermined time period to obtain a third product mixture comprising 2-amino-3-trifluoromethylbenzoic acid and separating 2-amino-3-trifluoromethylbenzoic acid from the third product mixture;
iv. diazotizing 2-amino-3-trifluoromethylbenzoic acid by using a first diazotizing agent in a fourth fluid medium at a fourth predetermined temperature for a fourth predetermined time period followed by halogenating by using a halogenating agent at a fifth predetermined temperature for a fifth predetermined time period to obtain a fourth product mixture comprising 2-bromo-3-trifluoromethylbenzoic acid and separating 2-bromo-3-trifluoromethylbenzoic acid from the fourth product mixture;
v. chlorinating 2-bromo-3-trifluoromethylbenzoic acid by using a first chlorinating agent in a fifth fluid medium in the presence of a catalyst at a sixth predetermined temperature for a sixth predetermined time period followed by amidating by using ammonia at a seventh predetermined temperature for a seventh predetermined time period to obtain a fifth product mixture comprising 2-bromo-3-trifluoromethylbenzamide and separating 2-bromo-3-trifluoromethylbenzamide from the fifth product mixture;
vi. oxidizing 2-bromo-3-trifluoromethylbenzamide by using a second oxidizing agent in a sixth fluid medium at an eighth predetermined temperature for an eighth predetermined time period to obtain a sixth product mixture comprising 2-bromo-3-trifluoromethyl aniline and separating 2-bromo-3-trifluoromethyl aniline from the sixth product mixture;
vii. diazotizing 2-bromo-3-trifluoromethyl aniline using a second diazotizing agent at a ninth predetermined temperature for a ninth predetermined time period followed by hydrolysis in a seventh fluid medium at a tenth predetermined temperature for a tenth predetermined time period to obtain 2-bromo-3-trifluoromethyl phenol;
viii. condensing 2-bromo-3-trifluoromethyl phenol with 2,2-difluroethyl methanesulfonate by using a base in an eighth fluid medium at an eleventh predetermined temperature for an eleventh predetermined time period to obtain a seventh product mixture comprising 2-bromo-1-(2,2-difluoroethoxy)-3-(trifluoromethyl)benzene and separating 2-bromo-1-(2,2-difluoroethoxy)-3-(trifluoromethyl)benzene from the seventh product mixture;
ix. reacting 2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl)benzene with a salt of ethyl mercaptan in a ninth fluid medium at a twelfth predetermined temperature for a twelfth predetermined time period to obtain an eighth product mixture comprising 2-ethylthio-3-(2,2-difluoroethoxy)benzotrifluoride and separating 2-ethylthio-3-(2,2-difluoroethoxy)benzotrifluoride from the eighth product mixture; and
x. oxidative chlorinating 2-(2,2,difluoroethoxy)-6-(trifluoromethyl)phenyl)(ethyl)sulfane by using a oxidative chlorinating agent at a thirteenth predetermined temperature for a thirteenth predetermined time period to obtain a ninth product mixture comprising 2-(2,2-difluoroethoxy)-6-(Trifluoromethyl)benzene sulfonyl chloride and separating 2-(2,2-difluoroethoxy)-6-(Trifluoromethyl)benzene sulfonyl chloride from the ninth product mixture.

The process is described in detail below:
Step I: Preparation of o-trifluoromethylisonitrosoacetanilide by using o-aminobenzotrifluoride
In a first step, o-aminobenzotrifluoride is reacted with hydroxylamine salt and chloral hydrate in a first fluid medium by using a alkali metal salt and a first acid at a first predetermined temperature for a first predetermined time period to obtain a first product mixture comprising o-trifluoromethyl-isonitroso acetanilide and separating o-trifluoromethyl-isonitroso acetanilide is separated from the first product mixture.
In this step, a predetermined amount of water and a predetermined amount of chloral hydrate are mixed at a temperature in the range of 20°C to 35°C to obtain a chloral hydrate solution. A predetermined amount of alkali metal salt and hydroxylamine salt are added at a temperature in the range of 20°C to 35°C to the chloral hydrate solution to obtain a first mixture. A predetermined amount of o-aminobenzotrifluoride (OABTF) is added to the first mixture followed by the addition of first acid under stirring to obtain a reaction mass. The reaction mass is heated at a first predetermined temperature for a first predetermined time period to obtain a first product mixture comprising o-aminobenzotrifluoride.
The first product mixture is cooled to a temperature in the range of 20 °C to 30 °C, followed by the addition of 2000 ml to 3000ml of a second fluid medium to obtain a biphasic mixture comprising an organic layer and an aqueous layer. The organic layer is separated and washed with water, followed by distillation at a temperature in the 75 °C to 90 °C under atmospheric pressure to obtain a concentrated mass of o-trifluoromethyl-isonitrosoacetanilide.
The o-trifluoromethyl-isonitrosoacetanilide concentrated mass was used as such for the preparation of 7-trifluoromethylisatin preparation.
In an embodiment of the present disclosure, the first predetermined temperature is in the range of 70°C to 100 °C. In an exemplary embodiment of the present disclosure, the first predetermined temperature is 80 °C.
In an embodiment of the present disclosure, the first predetermined time period is in the range of 3 hours to 5 hours. In an exemplary embodiment of the present disclosure, the time period is in the range of 4 hours.
The hydroxylamine salt is selected from the group consisting of hydroxylamine sulphate, hydroxylamine hydrochloride. In an exemplary embodiment, the hydroxylamine salt is hydroxylamine sulphate.
The first fluid medium is water.
The first acid is selected from the group consisting of hydrochloric acid, and sulfuric acid. In an exemplary embodiment, the first acid is hydrochloric acid.
As an exemplary embodiment, a schematic representation for the preparation of o-trifluoromethyl-isonitrosoacetanilide is given as scheme A,

SCHEME A
STEP II: Preparation of 7-trifluoromethylisatin
o-trifluoromethyl-isonitrosoacetanilide is cyclized by using a second acid in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain a second product mixture comprising 7-trifluoromethylisatin and 7-trifluoromethylisatin is separated from the second product mixture.
In this step, a predetermined amount of second acid is heated at a temperature in the range of 50 °C to 60 °C followed by the addition of a predetermined amount of solution of o-trifluoromethyl-isonitrosoacetanilide in a second fluid medium at a second predetermined temperature for a time period in the range of 40 minutes to 50 minutes to obtain a solution. The solution was equilibrated at a second predetermined temperature for a second predetermined time period to obtain a second product mixture comprising 7-trifluoromethylisatin. 7-trifluoromethylisatin is separated from the second product mixture.
The second acid is selected from the group consisting of sulphuric acid, methane sulfonic acid, trifluoroacetic acid and triflic acid. In an exemplary embodiment, the second acid is sulphuric acid.
The second fluid medium is selected from the group consisting of ethylene dichloride, methylene dichloride and chlorobenzene. In an exemplary embodiment, the second fluid medium is ethylene dichloride.
The second predetermined temperature is in the range of 40 °C to 60 °C. In an exemplary embodiment, the second predetermined temperature is 55 °C.
The second predetermined time period is in the range of 3 hours to 10 hours. In an exemplary embodiment, the second predetermined time period is 6 hours.
As an exemplary embodiment, a schematic representation for the preparation of 7-trifluoromethylisatin is given as scheme B,

SCHEME B
STEP III: Preparation of 2-amino-3-trifluoromethylbenzoic acid
7-trifluoromethylisatin is oxidized by using a first oxidizing agent in a third fluid medium at a third predetermined temperature for a third predetermined time period to obtain a third product mixture comprising 2-amino-3-trifluoromethylbenzoic acid. 2-amino-3-trifluoromethylbenzoic acid is separated from the third product mixture to obtain 2-amino-3-trifluoromethylbenzoic acid.
In this step, a predetermined amount of sodium hydroxide solution and a predetermined amount of 7-trifluoromethylisatin are mixed under stirring to obtain a slurry. The slurry is cooled to a temperature in the range of 10 °C to 20 °C followed by the addition of a predetermined amount of first oxidizing agent at a temperature in the range of 10 °C to 20 °C and stirred for a time period in the range of 0.5 hours to 2 hours to obtain a reaction mass. The reaction mass is maintained at a third predetermined temperature for a third predetermined time period to obtain a third product mixture comprising 2-amino-3-trifluoromethylbenzoic acid (ATFMBA).
2-amino-3-trifluoromethylbenzoic acid is separated from the third product mixture to obtain 2-amino-3-trifluoromethylbenzoic acid.
The third fluid medium is water.
The third predetermined temperature is in the range of 10 °C to 30 °C. In an exemplary embodiment, the third predetermined temperature is 20 °C.
The third predetermined time period is in the range of 4 hours to 15 hours. In an exemplary embodiment, the third predetermined time period is 5.5 hours.
As an exemplary embodiment, a schematic representation for the preparation of 2-amino-3-trifluoromethylbenzoic acid (ATFMBA) is given as scheme C,

SCHEME C
STEP IV: Preparation of 2-bromo-3-trifluoromethylbenzoic acid
2-amino-3-trifluoromethylbenzoic acid is diazotized by using a first diazotizing agent in a fourth fluid medium at a fourth predetermined temperature for a fourth predetermined time period followed by halogenation by using a halogenating agent at a fifth predetermined temperature for a fifth predetermined time period to obtain a fourth product mixture comprising 2-bromo-3-trifluoromethylbenzoic acid and separating 2-bromo-3-trifluoromethylbenzoic acid from said fourth product mixture.
In this step, a predetermined amount of aqueous hydrobromic acid is mixed with a predetermined amount of 2-amino-3-trifluoromethylbenzoic acid (ATFMBA) to obtain a first mixture. A predetermined amount of sodium nitrite or potassium nitrite in a predetermined amount of fourth fluid medium is added to the first mixture at a fourth predetermined temperature for a time period in the range of 2 hours to 6 hours to obtain a second mixture. The second mixture is maintained at fourth predetermined temperature for a fourth predetermined time period followed by cooling at a temperature in the range of 10 °C to 20 °C to obtain a cooled second mixture.
Maintaining the temperature in the range of 20 °C to 35 °C, the cooled second mixture is slowly mixed with halogenating agent for a time period in the range of 1 hour to 5 hours and equilibrated at fifth predetermined temperature for a fifth predetermined time period to obtain a product mixture comprising 2-bromo-3-trifluoromethylbenzoic acid.
The first diazotizing agent is selected from the group consisting of a mixture of sodium nitrite, potassium nitrite, hydrobromic acid and a mixture of potassium nitrite and, hydrobromic acid. In an exemplary embodiment, the first diazotizing agent is a mixture of sodium nitrite and hydrobromic acid.
The fourth fluid medium is selected from the group consisting of water.
The halogenating agent is a metal halide selected from the group consisting of CuBr
The fourth predetermined temperature is in the range of 20 °C to 40°C. In an exemplary embodiment, the fourth predetermined temperature is 25 °C.
The fourth predetermined time period is in the range of 0.5 hours to 3 hours. In an exemplary embodiment, the fourth predetermined time period is 1 hour.
The fifth predetermined temperature is in the range of 20 °C to 40°C. In an exemplary embodiment, the fifth predetermined temperature is 25 °C.
The fifth predetermined time period is in the range of 5 hours to 15 hours. In an exemplary embodiment, the fifth predetermined time period is 7.5 hours
As an exemplary embodiment, a schematic representation for the preparation of 2-bromo-3-trifluoromethylbenzoic acid (BTFMBA) is given as scheme D,

SCHEME D
STEP V: Preparation of 2-bromo-3-trifluoromethylbenzamide
2-bromo-3-trifluoromethylbenzoic acid is chlorinated by using a first chlorinating agent in a fifth fluid medium in the presence of a catalyst at a sixth predetermined temperature for a sixth predetermined time period followed by amidating by using ammonia at a seventh predetermined temperature for a seventh predetermined time period to obtain a fifth product mixture comprising 2-bromo-3-trifluoromethylbenzamide and separating 2-bromo-3-trifluoromethylbenzamide from the fifth product mixture .
Predetermined amounts of fifth fluid medium and 2-bromo-3-trifluoromethylbenzoic acid (BTFMBA) are mixed under stirring to obtain a first mixture. A predetermined amount of catalyst is added to the first mixture and heated at a temperature in the range of 55 °C to 65 °C to obtain a second mixture. A first chlorinating agent is added to the second mixture at a temperature in the range of 55 °C to 65 °C and stirred for a time period in the range of 1 hour to 5 hours to obtain a third mixture. The third mixture is heated at a sixth predetermined temperature and maintained at sixth predetermined temperature for a sixth predetermined time period to obtain a fourth mixture. The fourth mixture is cooled to a temperature in the range of 20 °C to 20 °C to obtain a resultant mass.
The resultant mass is mixed with a predetermined amount of ammonia solution slowly for a time period in the range of 0.5 hours to 2 hours and maintained at a temperature in the range of 5°C to 10°C to obtain a slurry. The slurry is equilibrated at seventh predetermined temperature for a seventh predetermined time period to obtain a fifth product mixture comprising 2-bromo-3-trifluoromethylbenzamide. 2-bromo-3-trifluoromethylbenzamide is separated from the fifth product mixture.
The first chlorinating agent is selected from the group consisting of thionyl chloride and oxalyl chloride. In an exemplary embodiment, the first chlorinating agent is thionyl chloride.
The fifth fluid medium is selected from the group consisting of toluene, benzene and mono chloro benzene. In an exemplary embodiment, the fifth fluid medium is toluene.
The catalyst is selected from the group consisting of dimethyl formamide and pyridine. In an exemplary embodiment, the catalyst is dimethyl formamide.
The sixth predetermined temperature is in the range of 50 °C to 90°C. In an exemplary embodiment, the sixth predetermined temperature is 80°C.
The sixth predetermined time period is in the range of 2 hours to 8 hours. In an exemplary embodiment, the sixth predetermined time period is 4 hours.
The seventh predetermined temperature is in the range of 5 °C to 20 °C. In an exemplary embodiment, the seventh predetermined temperature is 10 °C.
The seventh predetermined time period is in the range of 0.5 hours to 5 hours. In an exemplary embodiment, the seventh predetermined time period is 2 hours.
As an exemplary embodiment, a schematic representation for the preparation of 2-bromo-3-trifluoromethylbenzamide is given as scheme E,

SCHEME E
STEP VI: Preparation of 2-bromo-3-trifluoromethyl aniline
2-bromo-3-trifluoromethyl benzamide is oxidized by using a second oxidizing agent in a sixth fluid medium at an eighth predetermined temperature for an eighth predetermined time period to obtain a sixth product mixture comprising 2-bromo-3-trifluoromethyl aniline and separating 2-bromo-3-trifluoromethyl aniline from the sixth product mixture
A predetermined amount of aqueous alkali solution is cooled to a temperature in the range of -2 °C to 5 °C to obtain a cooled first mixture. A predetermined amount of bromine is slowly added to the cooled first mixture for a time period in the range of 20 minutes to 40 minutes to obtain a cooled reducing agent mixture.
A predetermined amount of BTFMBz is slowly added to the cooled reducing agent mixture for a time period in the range of 25 minutes to 35 minutes and maintained at a temperature in the range of -2 °C to 5 °C for a time period in the range of 0.5 hours to 3 hours to obtain a reaction mass. The reaction mass is heated at an eighth predetermined temperature for an eighth predetermined time period to obtain a product mass comprising 2-bromo-3-trifluoromethyl aniline (BTFMA). 2-bromo-3-trifluoromethyl aniline (BTFMA) is separated from the product mass.
The second oxidizing is selected from the group consisting of potassium hydroxide and bromine, sodium hydroxide and bromine and sodium hydroxide and chlorine. In an exemplary embodiment, the reducing agent is potassium hydroxide and bromine. 2-bromo-3-trifluoromethyl aniline is oxidized by Hoffmann reaction.
The sixth fluid medium is selected from the group consisting of water.
The eighth predetermined temperature is in the range of 80 °C to 100 °C. In an exemplary embodiment, the eighth predetermined temperature is 95 °C.
The eighth predetermined time period is in the range of 0.5 hours to 5 hours. In an exemplary embodiment, the eighth predetermined time period is 2 hours.
As an exemplary embodiment, a schematic representation for the preparation of 2-bromo-3-trifluoromethyl aniline is given as scheme F,

SCHEME F
STEP VII: Preparation of 2-bromo-3-trifluoromethyl phenol
2-bromo-3-trifluoromethyl aniline is diazotized by using a second diazotizing agent at a ninth predetermined temperature for a ninth predetermined time period followed by hydrolysis in a seventh fluid medium at a tenth predetermined temperature for a tenth predetermined time period.
In this step, a predetermined amount of acid is cooled at a temperature in the range 0 oC to 5 oC followed by the addition of a predetermined amount of 2-bromo-3-trifluoromethyl aniline (BTFMA) at a temperature in the range of 0°C to 5°C under stirring for a time period in the range of 20 minutes to 30 minutes and further maintained at a temperature in the range of 0 °C to 5 °C for a time period in the range of 20 minutes to 30 minutes to obtain a first mixture. Maintaining the temperature, a predetermined amount of sodium nitrite is added to the first mixture for a time period in the range of 50 minutes to 70 minutes and further maintained at a ninth predetermined temperature in the range for a ninth predetermined time period to obtain diazonium salt.
Separately a predetermined amount of sulfuric acid and copper sulphate is heated at a tenth predetermined temperature to obtain a second mixture. To the second mixture, the diazonium salt is slowly added at a tenth predetermined temperature for a tenth predetermined time period with simultaneous steam distillation of 2-bromo-3-trifluoromethyl phenol.
The ninth predetermined temperature is in the range of -2 °C to 10 °C. In an exemplary embodiment, the ninth predetermined temperature is 0 °C.
The ninth predetermined time period is in the range of 30 minutes to 60 minutes. The ninth predetermined time period is 45 minutes.
The tenth predetermined temperature is in the range of 120 °C to 150 °C. The tenth predetermined temperature is 135 °C.
The ninth predetermined time period is in the range of 2 hours to 6 hours. The ninth predetermined time period is 3.5 hours.
As an exemplary embodiment, a schematic representation for the preparation of 2-bromo-3-trifluoromethyl phenol is given as scheme G,

SCHEME G
STEP VIII: Preparation of 2-bromo-1-(2,2,-difluoroethoxy)-3-(trifluoromethyl) benzene
2-bromo-1-(2,2,-difluoroethoxy)-3-(trifluoromethyl) benzene having the following structure

2-bromo-3-trifluoromethyl phenol is condensed with 2,2-difluroethyl methanesulfonate by using a second base in an eighth fluid medium at an eleventh predetermined temperature for an eleventh predetermined time period to obtain a seventh product mixture comprising 2-bromo-1-(2,2-difluoroethoxy)-3-(trifluoromethyl)benzene.2-bromo-1-(2,2-difluoroethoxy)-3-(trifluoromethyl)benzene is separated from the seventh product mixture to obtain 2-bromo-1-(2,2-difluoroethoxy)-3-(trifluoromethyl) benzene.
Predetermined amounts of eighth fluid medium, second base, 2-bromo-3-trifluoromethyl phenol are mixed to obtain a first mixture. The first mixture is heated at a temperature in the range of 110 °C to 130 °C followed by slow addition of predetermined amount of 2, 2-dilfuoroethyl methane sulfonate in a time period in the range of 1 hours to 3 hours and further maintained at an eleventh predetermined temperature for an eleventh predetermined time period to obtain a seventh product mixture comprising 2-bromo-1-(2, 2, difluoroethoxy)-3-(trifluoromethyl) benzene.
The second base is selected from the group consisting of potassium carbonate and sodium carbonate. In an exemplary embodiment, the base is potassium carbonate.
The eighth fluid medium is selected from the group consisting of dimethylformamide and N,N-dimethylacetamide. In an exemplary embodiment, the eighth fluid medium is dimethylformamide.
The eleventh predetermined temperature is in the range of 100 °C to 130°C. In an exemplary embodiment, the eleventh predetermined temperature is 120 °C.
The eleventh predetermined time period is in the range of 1 hour to 6 hours. In an exemplary embodiment, the eleventh predetermined time period is 3.5 hours.
As an exemplary embodiment, a schematic representation for the preparation of 2-bromo-1-(2, 2, difluoroethoxy)-3-(trifluoromethyl) benzene is given as scheme H,

SCHEME H
STEP IX: Preparation of 2-Ethylthio-3-(2,2, difluoroethoxy) benzotrifluoride
2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl)benzene is reacted with a salt of ethyl mercaptan in a ninth fluid medium at a twelfth predetermined temperature for a twelfth predetermined time period to obtain an eighth product mixture comprising 2-ethylthio-3-(2,2-difluoroethoxy)benzotrifluoride and 2-ethylthio-3-(2,2-difluoroethoxy)benzotrifluoride is separated from the eighth product mixture.
Predetermined amounts of ninth fluid medium, a salt of ethyl mercaptan and 2-bromo-1-(2, 2, difluoroethoxy)-3-(trifluoromethyl) benzene are mixed to obtain a mixture. The mixture is heated at a twelfth predetermined temperature for a twelfth predetermined time period to obtain an eighth product mixture comprising 2-ethylthio-3-(2,2-difluoroethoxy)benzotrifluoride. The ninth fluid medium is distilled from the eighth product mixture to obtain 2-ethylthio-3-(2,2-difluoroethoxy) benzotrifluoride.
The salt of ethyl mercaptan is selected from the group consisting of sodium salt of ethyl mercaptan, potassium salt of ethyl mercaptan and lithium salt of ethyl mercaptan .In an exemplary embodiment the salt of ethyl mercaptan is sodium salt of ethyl mercaptan.
The ninth fluid medium is selected from the group consisting of N,N-dimethylacetamide, ethylene glycol dimethyl ether, N-methyl pyrrolidone and dimethylsulfoxide. In an exemplary embodiment, the ninth fluid medium is dimethylformamide.
The twelfth predetermined temperature is in the range of 70 °C to 90°C. In an exemplary embodiment, the twelfth predetermined temperature is 75 °C.
The twelfth predetermined time period is in the range of 5 hours to 8 hours. In an exemplary embodiment, the twelfth predetermined time period is 6 hours.
The weight ratio of 2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl) benzene and salt of ethyl mercaptan is in the range of 2:1 to 4:1. In an exemplary embodiment, the weight ratio of 2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl) benzene and salt of ethyl mercaptan is 3:1.
As an exemplary embodiment, a schematic representation for the preparation of 2-ethylthio-3-(2,2-difluoroethoxy) benzotrifluoride is given as scheme I,

SCHEME I
STEP X: Preparation of 2-(2, 2-difluoroethoxy)-6-(trifluoromethyl) benzenesulfonyl chloride
Oxidative chlorination of 2-(2,2,difluoroethoxy)-6-(trifluoromethyl)phenyl)(ethyl)sulfane by using a oxidative chlorinating agent at a thirteenth predetermined temperature for a thirteenth predetermined time period to obtain a ninth product mixture comprising 2-(2,2-difluoroethoxy)-6-(Trifluoromethyl)benzene sulfonyl chloride. 2-(2,2-difluoroethoxy)-6-(Trifluoromethyl) benzene sulfonyl chloride is separated from the ninth product mixture.
In this step, a predetermined amount of an acid , 2-ethylthio-3-(2,2-difluoroethoxy)benzotrifluoride (82% purity) is heated to a thirteenth predetermined temperature for a thirteenth predetermined time period to obtain a first mixture. To the first mixture, a predetermined amount of chlorine is added at a fourteenth predetermined temperature for a fourteenth predetermined time period to obtain a ninth mixture comprising 2-(2,2-difluoroethoxy)-6-(trifluoromethyl)benzene sulfonyl chloride.
The oxidative chlorinating agent is selected from the group consisting of acetic acid and chlorine, formic acid, monochloroacetic acid mother liquor and chlorine. In an exemplary embodiment, the oxidative chlorinating agent is acetic acid and chlorine.
The thirteenth predetermined temperature is in the range of 30 °C to 50°C. In an exemplary embodiment, the thirteenth predetermined temperature is 45°C.
The thirteenth predetermined time period is in the range of 0.5 hours to 3 hours. In an exemplary embodiment, the fourteenth predetermined time period is 1 hour.
As an exemplary embodiment, a schematic representation for the preparation of 2-(2, 2-difluoroethoxy)-6-(trifluoromethyl) benzenesulfonyl chloride is given as scheme J,

SCHEME J
The present disclosure provides a simple, economic, and efficient process for the preparation of penoxsulam intermediate (2-(2,2-difluoroethoxy)-6-(trifluoromethyl) benzene sulfonyl chloride) which provides a comparatively higher yield of the product with greater purity.
The foregoing description of the embodiments has been provided for purposes of illustration and is not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.
The present disclosure is further described in light of the following experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. The following experiments are scalable to industrial/commercial process.
EXPERIMENTAL DETAILS
EXAMPLE 1: Process for preparation of 2-(2,2-difluoroethoxy)-6-(trifluoromethyl) benzene sulfonyl chloride
Step I: Preparation of o-trifluoromethyl-isonitrosoacetanilide
EXPERIMENT 1:
In a reactor, 8325 ml of water was charged followed by adding 363 gm of chloral hydrate at 20°C to 25°C to obtain a chloral hydrate solution. 739.4 gm of sodium sulphate was added to the chloral hydrate solution at 20°C to 25°C followed by adding 508 gm of hydroxylamine sulphate to obtain a first mixture. Maintaining the temperature at 20°C to 25°C, 241.5 gm (1.5 m) of o-aminobenzotrifluoride (OABTF) was added to the first mixture followed by adding 135 ml of 10N HCl under stirring to obtain a reaction mass. The reaction mass was heated to 80°C and maintained for 4 hours to obtain a product mass comprising o-aminobenzotrifluoride
The so obtained product mass was cooled to 25°C, followed by adding 2250 ml of ethylene dichloride (EDC) to obtain a biphasic mixture comprising an organic layer and an aqueous layer. The organic layer was separated and washed with water, followed by distillation at 80°C to 85°C under atmospheric pressure to obtain o-trifluoromethyl-isonitrosoacetanilide.
The o-trifluoromethyl-isonitrosoacetanilide concentrated mass was used as such for 7-trifluoromethylisatin preparation. The yield of o-trifluoromethyl-isonitrosoacetanilide is 313 gm in 450ml EDC.
Step II: Preparation of 7-trifluoromethylisatin
EXPERIMENT 2:
900 ml of sulfuric acid (98%) was charged into a reactor and heated to 55°C followed by adding a solution of 313gm of o-trifluoromethyl-isonitrosoacetanilide in 450ml EDC obtained in Experiment 1 at 55 oC for 45 minutes to obtain a solution. The solution was equilibrated at 55°C for 5 hours to obtain a product mixture comprising 7-trifluoromethylisatin.
The product mixture comprising 7-trifluoromethylisatin was cooled to 25°C and maintained for settling for 30 min to obtain a biphasic mixture containing an EDC layer and an aqueous layer. The EDC layer from the biphasic mixture was separated followed by drawing of the aqueous layer in 2500 ml/m H2O which was equilibrated at 25oC to 30oC for 1 hour to obtain a slurry. The so obtained slurry was filtered to obtain a wet cake. The wet cake was washed thrice with 300 ml of water (each washing) followed by drying to obtain 7-trifluoromethylisatin.
The yield of 7-trifluoromethylisatin was 248 gm, the HPLC purity was 93.2% and the yield on purity was 71.6% on OABTF (o-aminobenzotrifluoride).
Step III: Preparation of 2-amino-3-trifluoromethylbenzoic acid
EXPERIMENT 3:
1330 gm of 10% of NaOH solution was charged into a reactor followed by adding 240 gm of 7-trifluoromethylisatin under stirring to obtain a slurry. The slurry was cooled to 15°C followed by adding 135 gm of 30% hydrogen peroxide at 15°C to 18°C for 2 hours to obtain a reaction mass. The reaction mass was equilibrated at 20°C to 22°C for 5 hours 30 minutes to obtain a third product mixture comprising 2-amino-3-trifluoromethylbenzoic acid.
The so obtained third product mixture was filtered to obtain a first filtrate. The process of filtration removes impurities from the second reaction mass.
The first filtrate was acidified using 160 ml 10N sulphuric acid to obtain a hazy solution. The so obtained hazy solution was extracted with EDC to remove impurities.
The aqueous layer was acidified by adding 168 ml of acetic acid to a pH of 5.2 followed by filtration to obtain a wet cake. The wet cake was washed with water to remove inorganic salts from cake and dried to obtain 2-amino-3-trifluoromethylbenzoic acid.
The yield of 2-amino-3-trifluoromethylbenzoic acid was 177 gm, the HPLC purity was 97.56% and the yield on purity was 88.7%.
Step IV: Process for the preparation of 2-bromo-3-trifluoromethylbenzoic acid
EXPERIMENT 4:
607.5 gm of aq. HBr (20%) was charged into a reactor followed by adding 123 gm of 2-amino-3-trifluoromethylbenzoic acid to obtain a first mixture (yellow coloured slurry). A solution of 64 gm of sodium nitrite (NaNO2) in 75 ml of water, was added to the first mixture at 25 °C for 4 hours to obtain a second mixture. The second mixture was maintained at 25 °C for 1 hour followed by cooling to 15°C to obtain a cooled second mixture.
Separately 244 gm of aq. HBr and 47.35 gm of CuBr were mixed at 25°C under stirring for 30 minutes to obtain a third mixture of HBr and CuBr. Maintaining the temperature at 25 °C, the so obtained cooled second mixture was slowly mixed with the third mixture of HBr and CuBr for 2 hours and equilibrated at 25°C for 5 hours 30 minutes to obtain a product mixture comprising 2-bromo-3-trifluoromethylbenzoic acid.
The product mixture was filtered, washed with water, and dried to obtain 2-bromo-3-trifluoromethylbenzoic acid.
The yield of 2-bromo-3-trifluoromethylbenzoic acid was 145 gm, the HPLC purity was 97% and the yield on purity was 87.14%.
Step V: Process for the preparation of 2-bromo-3-trifluoromethylbenzamide
EXPERIMENT 5:
625 ml of toluene was charged into a reactor followed by adding 136.5 gm of 2-bromo-3-trifluoromethylbenzoic acid under stirring to obtain a first mixture. 2.5 ml of DMF was added to the first mixture and heated to 60°C to obtain a second mixture. Thionyl chloride was added to the second mixture at 60°C, 89.3 gm for 4 hours to obtain a third mixture. The third mixture was heated to 80°C and maintained at 80oC for 4 hours to obtain a fourth mixture. The fourth mixture was cooled to 25°C to obtain a resultant mass.
The so obtained resultant mass was drowned into 250 ml of 6N ammonia solution slowly for 1 hour maintaining a temperature of 5°C to obtain a slurry. The slurry was equilibrated at 10°C for 1 hour followed by filtration and washing and drying to obtain 2-bromo-3-trifluoromethylbenzamide.
The yield of 2-bromo-3-trifluoromethylbenzamide was 114-118 gm, the HPLC purity was >98% % and the yield on purity was 85-87%.
Step VI: Preparation of 2-bromo-3-trifluoromethyl aniline
EXPERIMENT 6:
456 gm of 8-10% aqueous KOH solution was charged into a reactor and cooled to 0°C to obtain a cooled first mixture. 27 gm of bromine was slowly added to the cooled first mixture for 30 minutes to obtain a cooled reducing agent mixture. 40.2gm of BTFMBz was slowly added to the cooled reducing agent mixture for 30 minutes maintaining at 0°C for 1 hour to obtain a reaction mass. The reaction mass was heated to 95°C and maintained for 2 hours (for mild reflux) to obtain a product mass comprising 2-bromo-3-trifluoromethyl aniline. The product mass comprising 2-bromo-3-trifluoromethyl aniline was cooled to 40°C, followed by extracting with (EDC). The (EDC) layer was separated washed with 100 ml of water followed by concentration to obtain 2-bromo-3-trifluoromethyl aniline.
The yield of 2-bromo-3-trifluoromethyl aniline was 36.4 gm, the HPLC purity was 89%% and the yield on purity was 90%.
Step VII: Preparation of 2-bromo-3-trifluoromethyl phenol
EXPERIMENT 7:
173 gm of sulfuric acid (52%) was charged into a reactor and the reactor is cooled to 0oC to 5oC followed by adding 49 gm of 2-bromo-3-trifluoromethyl aniline at 0 °C under stirring 30 min and further maintained at 0°C to 5°C for 30 minutes to obtain a first mixture. Maintaining the temperature, 13.7 gm of sodium nitrite solution (26%) was added to the first mixture for 60 minutes and further maintained at 0 °C for 45 minutes to obtain diazonium salt.
Separately 106 gm of sulfuric acid (66%) was charged into a reactor followed by adding 5.84 gm of copper sulphate pentahydrate (CuSO4.5H2O) and heated to reflux temperature at 135°C to obtain a second mixture. To the second mixture, the first mixture was slowly added at 135°C over 3.5 hours, with simultaneous steam distillation of 2-bromo-3-trifluoromethyl phenol. 2-bromo-3-trifluoromethyl phenol was distilled to obtain 2-bromo-3-trifluoromethyl phenol.
The yield of 2-bromo-3-trifluoromethyl phenol was 34.3 gm, and the purity was 94.43%.
The yield on the purity of 2-bromo-3-trifluoromethyl phenol was 74.58%.
Preparation of 2,2-Difluoroethyl methane sulfonate
EXPERIMENT 8:
Separately 2,2-Difluoroethyl methane sulfonate was prepared.
300ml of methylene dichloride (MDC) was charged in a reactor followed by adding 137 gm of methane sulfonyl chloride to obtain a reaction mass. The reaction mass was cooled to 5°C followed by adding 82 gm of 2,2-difluoroethanol and further cooled to 0°C to obtain a reaction mixture. 151.5 gm of triethyl amine (TEA) was added in 3.25 hrs to the first reaction mixture by maintaining reaction mass temperature 0-2°C. After the complete addition of TEA, the temperature of the reaction mixture was raised to 27°C and maintained for 1hr to obtain a product mass comprising 2,2-Difluoroethyl methane sulfonate.
The product mass was drowned in 400ml water and pH was adjusted by using 10N HCl from 9 to 5.8 to obtain a slurry. The slurry was equilibrated for 30 minutes and layers were separated comprising an aqueous layer and an organic layer. The aqueous layer was extracted twice with 100ml MDC (each washing). The organic layer (MDC layer) was separated, mixed with both organic layers, and washed with 200ml water. The organic layer was concentrated to dryness.
The yield of 2,2-Difluoroethyl methane sulfonate was 158.5g, HPLC purity was 95% and the yield on purity was 94.1%.
Step VIII: Preparation of 2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl) benzene
EXPERIMENT 9:
400 ml of DMF was charged into a reactor followed by adding 48.3 gm of potassium carbonate (K2CO3) and 85 gm of 2-bromo-3-trifluoromethyl phenol to obtain a first mixture. The first mixture was heated to 120°C followed by slowly adding 61.62 gm of 2,2-difluoroethyl methane sulfonate in 2 hours 15 minutes and further maintained at 120oC for 1 hour to obtain a reaction mass. The reaction mass was cooled to 25°C and filtered to obtain a filtrate comprising 2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl) benzene. The filtrate comprising 2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl)benzene was drowned in 200 ml of water and MDC to obtain a biphasic mixture comprising MDC layer (organic layer) and water layer (aqueous layer). The organic layer was separated and concentrated to obtain 2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl) benzene.
The yield of 2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl) benzene was 99.1 gm, the HPLC purity was 96.99% and the yield on purity was 91.33%.
Step IX: Preparation of 2-ethylthio-3-(2,2-difluoroethoxy) benzotrifluoride
EXPERIMENT 10:
2.79 gm of ethyl mercaptan in 200 ml methanol and 2.349 gm of NaOMe were mixed to obtain a mixture and the mixture was concentrated at 50-55 oC to obtain a residual mass comprising Na salt of ethyl mercaptan.
40 ml of DMF was charged into a reactor followed by adding 3.65 gm of sodium salt of ethyl mercaptan and 11 gm of 2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl) benzene to obtain a mixture and the mixture was heated to 75°C and maintained it for 6 hours to obtain a reaction mass. The reaction mass was distilled out at 75°C to remove DMF to obtain a product mass comprising 2-ethylthio-3-(2,2-difluoroethoxy)benzotrifluoride. The product mass comprising 2-ethylthio-3-(2,2-difluoroethoxy)benzotrifluoride was drowned in 100 ml of water followed by extracting the product in methylene dichloride (MDC) by using 100 ml of MDC (each) 2 times. The combined MDC extracts were washed with water followed by concentrating to obtain 2-ethylthio-3-(2,2-difluoroethoxy) benzotrifluoride.
The yield of 2-ethylthio-3-(2,2-difluoroethoxy) benzotrifluoride was 10.1 gm, the HPLC purity was 82% and the yield on purity was 96.5%.
Step X: Preparation of 2-(2,2-difluoroethoxy)-6-(trifluoromethyl) benzenesulfonyl chloride
EXPERIMENT 11:
33 gm of acetic acid (90%) was charged into a reactor followed by adding 4.1 gm of 2-ethylthio-3-(2,2-difluoroethoxy)benzotrifluoride (82% purity) and heated to 45°C to obtain a first mixture. To the first mixture, 6 m/m of chlorine gas was passed at 45°C for 1 hour to obtain a product mass comprising 2-(2,2-difluoroethoxy)-6-(trifluoromethyl)benzene sulfonyl chloride. The product mass comprising 2-(2,2-difluoroethoxy)-6-(trifluoromethyl) benzene sulfonyl chloride was drowned in cold water at 0-5°C and kept for 15 minutes followed by filtration to obtain 2-(2,2-difluoroethoxy)-6-(trifluoromethyl) benzene sulfonyl chloride.
The yield of 2-(2,2-difluoroethoxy)-6-(trifluoromethyl) benzene sulfonyl chloride was 3.36 gm, the HPLC purity was 95% and the yield on purity was 90%.
TECHNICAL ADVANCEMENT
The present disclosure described hereinabove has several technical advantages including, but not limited to, the realization of a process for the preparation of 2-(2,2-difluoroethoxy)-6-(trifluoromethyl) benzene sulfonyl chloride that
• uses less amount of solvents, and inexpensive reactants, hence economical;
• is simple and environment friendly; and
• provides 2-(2,2-difluoroethoxy)-6-(trifluoromethyl) benzene sulfonyl chloride having comparatively high purity and high yield.
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
The foregoing description of the specific embodiments so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the invention to achieve one or more of the desired objects or results. While certain embodiments of the inventions have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Variations or modifications to the formulation of this invention, within the scope of the invention, may occur to those skilled in the art upon reviewing the disclosure herein. Such variations or modifications are well within the spirit of this invention.
Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.
The numerical values given for various physical parameters, dimensions, and quantities are only approximate values and it is envisaged that the values higher than the numerical value assigned to the physical parameters, dimensions, and quantities fall within the scope of the invention unless there is a statement in the specification to the contrary.
While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation. ,CLAIMS:WE CLAIM:
1. A process for the preparation of 2-(2,2-difluoroethoxy)-6-(trifluoromethyl)benzene sulfonyl chloride, said process comprising the following steps:
i. reacting o-aminobenzotrifluoride with hydroxylamine salt and chloral hydrate in a first fluid medium by using a alkali metal salt and a first acid at a first predetermined temperature for a first predetermined time period to obtain a first product mixture comprising o-trifluoromethyl-isonitroso acetanilide and separating o-trifluoromethyl-isonitrosoacetanilide from said first product mixture;
ii. cyclizing o-trifluoromethyl-isonitrosoacetanilide by using a second acid in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain a second product mixture comprising 7-trifluoromethylisatin and separating 7-trifluoromethylisatin from said second product mixture;
iii. oxidizing 7-trifluoromethylisatin by using a first oxidizing agent in a third fluid medium at a third predetermined temperature for a third predetermined time period to obtain a third product mixture comprising 2-amino-3-trifluoromethylbenzoic acid and separating 2-amino-3-trifluoromethylbenzoic acid from said third product mixture;
iv. diazotizing 2-amino-3-trifluoromethylbenzoic acid by using a first diazotizing agent in a fourth fluid medium at a fourth predetermined temperature for a fourth predetermined time period followed by halogenating by using a halogenating agent at a fifth predetermined temperature for a fifth predetermined time period to obtain a fourth product mixture comprising 2-bromo-3-trifluoromethylbenzoic acid and separating 2-bromo-3-trifluoromethylbenzoic acid from said fourth product mixture;
v. chlorinating 2-bromo-3-trifluoromethylbenzoic acid by using a first chlorinating agent in a fifth fluid medium in the presence of a catalyst at a sixth predetermined temperature for a sixth predetermined time period followed by amidating by using ammonia at a seventh predetermined temperature for a seventh predetermined time period to obtain a fifth product mixture comprising 2-bromo-3-trifluoromethylbenzamide and separating 2-bromo-3-trifluoromethylbenzamide from said fifth product mixture;
vi. oxidizing 2-bromo-3-trifluoromethylbenzamide by using a second oxidizing agent in a sixth fluid medium at an eighth predetermined temperature for an eighth predetermined time period to obtain a sixth product mixture comprising 2-bromo-3-trifluoromethyl aniline and separating 2-bromo-3-trifluoromethyl aniline from said sixth product mixture;
vii. diazotizing 2-bromo-3-trifluoromethyl aniline using a second diazotizing agent at a ninth predetermined temperature for a ninth predetermined time period followed by hydrolysis in a seventh fluid medium at a tenth predetermined temperature for a tenth predetermined time period to obtain 2-bromo-3-trifluoromethyl phenol;
viii. condensing 2-bromo-3-trifluoromethyl phenol with 2,2-difluroethyl methanesulfonate by using a base in an eighth fluid medium at an eleventh predetermined temperature for an eleventh predetermined time period to obtain a seventh product mixture comprising 2-bromo-1-(2,2-difluoroethoxy)-3-(trifluoromethyl)benzene and separating 2-bromo-1-(2,2-difluoroethoxy)-3-(trifluoromethyl)benzene from said seventh product mixture;
ix. reacting 2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl)benzene with a salt of ethyl mercaptan in a ninth fluid medium at a twelfth predetermined temperature for a twelfth predetermined time period to obtain an eighth product mixture comprising 2-ethylthio-3-(2,2-difluoroethoxy)benzotrifluoride and separating 2-ethylthio-3-(2,2-difluoroethoxy)benzotrifluoride from said eighth product mixture; and
x. oxidative chlorinating 2-(2,2,difluoroethoxy)-6-(trifluoromethyl)phenyl)(ethyl)sulfane by using an oxidative chlorinating agent at a thirteenth predetermined temperature for a thirteenth predetermined time period to obtain a ninth product mixture comprising 2-(2,2-difluoroethoxy)-6-(trifluoromethyl)benzene sulfonyl chloride and separating 2-(2,2-difluoroethoxy)-6-(Trifluoromethyl)benzene sulfonyl chloride from said ninth product mixture.

2. The process as claimed in claim 1, wherein said hydroxylamine salt is selected from the group consisting of hydroxylamine sulphate and hydroxylamine hydrochloride; said first fluid medium is water; said alkali metal salt is selected from the group consisting of sodium sulphate and potassium sulphate; and said first acid is selected from the group consisting of hydrochloric acid and sulfuric acid.

3. The process as claimed in claim 1, wherein said first predetermined temperature is in the range of 70°C to 100°C; and said first predetermined time period is in the range of 3 hours to 5 hours.

4. The process as claimed in claim 1, wherein said second acid is selected from the group consisting of sulphuric acid, methanesulfonic acid, trifluoroacetic acid and triflic acid; and said second fluid medium is selected from the group consisting of ethylene dichloride, methylene dichloride and chlorobenzene.
5. The process as claimed in claim 1, wherein said second predetermined temperature is in the range of 40 °C to 60 °C; and said second predetermined time period is in the range of 3 hours to 10 hours.

6. The process as claimed in claim 1, wherein said first oxidizing agent is hydrogen peroxide; and said third fluid medium is water.

7. The process as claimed in claim 1, wherein said third predetermined temperature is in the range of 10 °C to 30 °C; and said third predetermined time period is in the range of 4 hours to 15 hours.

8. The process as claimed in claim 1, wherein said first diazotizing agent is selected from the group consisting of a mixture of sodium nitrite and hydrobromic acid and a mixture of potassium nitrite and hydrobromic acid; said fourth fluid medium is water; and said halogenating agent is a metal halide; wherein said metal halide is CuBr.

9. The process as claimed in claim 1, wherein said fourth predetermined temperature is in the range of 20 °C to 40°C; said fourth predetermined time period is in the range of 0.5 hour to 3 hours; said fifth predetermined temperature is in the range of 20 °C to 40°C; and said fifth predetermined time period is in the range of 5 hours to 15 hours.

10. The process as claimed in claim 1, wherein said first chlorinating agent is selected from the group consisting of thionyl chloride, and oxalyl chloride; said fifth fluid medium is selected from the group consisting of toluene, benzene and mono chloro benzene; and said catalyst is selected from the group consisting of dimethyl formamide and pyridine.

11. The process as claimed in claim 1, wherein said sixth predetermined temperature is in the range of 50 °C to 90°C; said sixth predetermined time period is in the range of 2 hours to 8 hours; said seventh predetermined temperature is in the range of 5 °C to 20 °C; and said seventh predetermined time period is in the range of 0.5 hour to 5 hours.

12. The process as claimed in claim 1, wherein said second oxidizing agent is selected from the group consisting of potassium hydroxide and bromine, sodium hydroxide and bromine, sodium hydroxide and chlorine and potassium hydroxide and chlorine; and said sixth fluid medium is water.

13. The process as claimed in claim 1, wherein said eighth predetermined temperature is in the range of 0 °C to 100 °C; and said eighth predetermined time period is in the range of 1 hour to 3 hours.

14. The process as claimed in claim 1, wherein said second diazotizing agent is sodium nitrite and sulphuric acid; said hydrolysis is carried out using sulfuric acid and copper sulphate; and said seventh fluid medium is water.

15. The process as claimed in claim 1, wherein said ninth predetermined temperature is in the range of -2 °C to 10 °C; said ninth predetermined time period is in the range of 30 minutes to 60 minutes; said tenth predetermined temperature is in the range of 120 °C to 150 °C and said tenth predetermined time period is in the range of 2 hours to 6 hours.

16. The process as claimed in claim 1, wherein said second base is selected from the group consisting of potassium carbonate and sodium carbonate; said eighth fluid medium is selected from the group consisting of dimethylformamide and N, N-dimethylacetamide.

17. The process as claimed in claim 1, wherein said eleventh predetermined temperature is in the range of 100 °C to 130°C; and said eleventh predetermined time period is in the range of 1 hour to 6 hours.

18. The process as claimed in claim 1, wherein said salt of ethyl mercaptan is selected from the group consisting of sodium salt of ethyl mercaptan, potassium salt of ethyl mercaptan and lithium salt of ethyl mercaptan; said ninth fluid medium is selected from the group consisting of dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, N-methyl pyrrolidone and dimethyl sulfoxide.

19. The process as claimed in claim 1, wherein said twelfth predetermined temperature is in the range of 70 °C to 90°C; and said twelfth predetermined time period is in the range of 5 hours to 8 hours.

20. The process as claimed in claim 1, wherein said oxidative chlorinating agent is selected from the group consisting of acetic acid and chlorine, formic acid and chlorine and monochloroacetic acid mother liquor and chlorine.

21. The process as claimed in claim 1, wherein said thirteenth predetermined temperature is in the range of 30 °C to 50°C; and said thirteenth predetermined time period is in the range of 0.5 hours to 3 hours.

22. The process as claimed in claim 1, wherein the weight ratio of 2-bromo-1-(2,2,difluoroethoxy)-3-(trifluoromethyl) benzene and salt of ethyl mercaptan is in the range of 2:1 to 4:1.

23. 2-bromo-1-(2,2-difluoroethoxy)-3-(trifluoromethyl)benzene having the structure

Dated this 30th Day of March, 2024

_______________________________
MOHAN RAJKUMAR DEWAN, IN/PA – 25
of R.K. DEWAN & CO.
Authorized Agent of Applicant

TO,
THE CONTROLLER OF PATENTS
THE PATENT OFFICE, AT MUMBAI