Description:FIELD
The present disclosure relates to a process for the preparation of 3-(difluoromethyl)-1-methyl-N-(3', 4’, 5’-trifluoro [1, 1’-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (Fluxapyroxad).
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
3-(difluoromethyl)-1-methyl-N-(3', 4’, 5’-trifluoro [1, 1’-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (Fluxapyroxad) is a broad-spectrum pyrazole-carboxamide fungicide used on a large variety of commercial crops. It prevents fungal growth on the crops by inhibiting succinate dehydrogenase enzyme, which results in inhibition of spore germination, germ tubes, and mycelial growth within the fungus target species. Fluxapyroxad is represented as formula (I) below:

Conventional methods for the preparation of fluxapyroxad are associated with drawbacks such as having impurities and a low yield of the product fluxapyroxad. Further, these conventional processes employ toxic and expensive reagents which make the process uneconomical. Still further, the conventional processes involve the use of organic bases which are harmful and difficult to separate.
Therefore, there is felt a need to provide a process for the preparation of fluxapyroxad that mitigates the aforestated drawbacks or at least provides a useful alternative.
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 background or to at least provide a useful alternative.
Another object of the present disclosure is to provide a process for the preparation of fluxapyroxad.
Yet another object of the present disclosure is to provide a process for the preparation of fluxapyroxad with a comparatively better purity and yield.
Still another object of the present disclosure is to provide a simple, cost-effective and environment friendly process for the preparation of fluxapyroxad.
Yet another object of the present disclosure is to provide a process for the preparation of fluxapyroxad that is commercially scalable.
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 Fluxapyroxad. The process comprises mixing 2-(3,4,5-trifluorophenyl)aniline and 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid in a first fluid medium at a first predetermined temperature for a first predetermined time period under stirring to obtain a first mixture. A dehydrating agent is slowly added to the first mixture under stirring at the first predetermined temperature over a second predetermined time period to obtain a second mixture. The second mixture is heated at a second predetermined temperature and stirred for a third predetermined time period to obtain a product mass comprising fluxapyroxad.

The first fluid medium is selected from the group consisting of xylene, toluene, acetonitrile, dichloromethane, ethylene dichloride and chlorobenzene.

The first predetermined temperature is in the range of 25 °C to 35 °C.

The first predetermined time period is in the range of 2 minutes to 10 minutes.

The dehydrating agent is selected from the group consisting of phosphorus trichloride and phosphorous pentoxide.

The second predetermined time period is in the range of 2 minutes to 20 minutes.

The second predetermined temperature is in the range of 80 °C to 125 °C.

The third predetermined time period is in the range of 2 hours to 10 hours.

The weight ratio of 2-(3,4,5-trifluorophenyl)aniline to 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is in the range of 0.5:1 to 3:1.

The yield of fluxapyroxad is in the range of 70% to 85% and purity is in the range of 97% to 99.9%.

DETAILED DESCRIPTION
The present disclosure relates to a process for the preparation of 3-(difluoromethyl)-1-methyl-N-(3', 4’, 5’-trifluoro [1, 1’-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (Fluxapyroxad).
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, known processes or well-known apparatus or 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 are 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 fluxapyroxad are associated with drawbacks such as having impurities and a low yield of the product fluxapyroxad. Further, these conventional processes employ toxic and expensive reagents which make the process uneconomical. Still further, the conventional processes involve the use of organic bases which are harmful and difficult to separate.
The present disclosure relates to a process for the preparation of 3-(difluoromethyl)-1-methyl-N-(3', 4’, 5’-trifluoro [1, 1’-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (Fluxapyroxad).
The process for preparing fluxapyroxad, comprises the following steps:
i. mixing 2-(3,4,5-trifluorophenyl)aniline and 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid in a first fluid medium at a first predetermined temperature for a first predetermined time period under stirring to obtain a first mixture;
ii. slowly adding a dehydrating agent in the first mixture under stirring at the first predetermined temperature over a second predetermined time period to obtain a second mixture; and
iii. heating the second mixture at a second predetermined temperature and stirred for a third predetermined time period to obtain a product mass comprising fluxapyroxad.
The process for preparing fluxapyroxad is described in detail herein below.
In a first step, a predetermined amount of 2-(3,4,5-trifluorophenyl)aniline and a predetermined amount of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid are mixed in a first fluid medium at a first predetermined temperature for a first predetermined time period under stirring to obtain a first mixture.
The weight ratio of 2-(3,4,5-trifluorophenyl)aniline to 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is in the range of 0.5:1 to 3:1. In an exemplary embodiment, the weight ratio of 2-(3,4,5-trifluorophenyl)aniline to 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is 1.1:1.
The first fluid medium is selected from the group consisting of xylene, toluene, acetonitrile, dichloromethane, ethylene dichloride and chlorobenzene. In an exemplary embodiment, the first fluid medium is xylene.
The first predetermined temperature is in the range of 25 °C to 35 °C. In an exemplary embodiment, the first predetermined temperature is 30 °C.
The first predetermined time period is in the range of 2 minutes to 10 minutes. In an exemplary embodiment, the first predetermined time period is 5 minutes.
In a second step, a dehydrating agent is slowly added to the first mixture under stirring at the first predetermined temperature over a second predetermined time period to obtain a second mixture.
The dehydrating agent is selected from the group consisting of phosphorus trichloride and phosphorous pentoxide. In an exemplary embodiment, the dehydrating agent is phosphorus trichloride.
The second predetermined time period is in the range of 2 minutes to 20 minutes. In an exemplary embodiment, the second predetermined time period is 10 minutes.
In an embodiment, the addition of dehydrating agent is carried out in a drop-wise manner.
In the conventional two step processes, acids are converted to amides by firstly converting acids to acid chlorides which are further converted to amides. The process of the present disclosure is a one-step reaction wherein acids are directly converted to amides by using a dehydrating agent. Therefore, the process of the present disclosure is economical.
In accordance with the present disclosure, the weight ratio of the mixture of 2-(3,4,5-trifluorophenyl)aniline and 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid to the dehydrating agent is in the range of 1.5:1 to 2.5:1. In an exemplary embodiment, the weight ratio of the mixture of 2-(3,4,5-trifluorophenyl)aniline and 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid to the dehydrating agent is 2:1.
In a third step, the second mixture is heated to a second predetermined temperature and stirred for a third predetermined time period to obtain a product mass comprising fluxapyroxad.
The second predetermined temperature is in the range of 80 °C to 125 °C. In an exemplary embodiment, the second predetermined temperature is 100 °C.
The third predetermined time period is in the range of 2 hours to 10 hours. In an exemplary embodiment, the third predetermined time period is 5 hours.
The product mass is cooled to a room temperature followed by the addition of a predetermined amount of water and stirring for a time period in the range of 5 minutes to 20 minutes to obtain a biphasic mixture.
The biphasic mixture is separated to obtain an organic layer containing fluxapyroxad and an aqueous layer. The organic layer is concentrated to obtain solids.
In an embodiment of the present disclosure, the solids obtained are slurried in a second fluid medium which is then filtered and dried to obtain fluxapyroxad.
The second fluid medium is selected from the group consisting of isopropyl alcohol, heptane, hexane and methyl tert-butyl ether. In an exemplary embodiment, the second fluid medium is isopropyl alcohol.
In accordance with the present disclosure, the yield of fluxapyroxad is in the range of 70% to 85%. In an exemplary embodiment, the yield of fluxapyroxad is 75%.
In accordance with the present disclosure, the purity of fluxapyroxad is in the range of 97% to 99.9%. In an exemplary embodiment, the purity of fluxapyroxad is 99.9%.
In accordance with an exemplary embodiment of the present disclosure, the schematic representation for the preparation of fluxapyroxad (I) is illustrated as below scheme:

Scheme-I
The process of the present disclosure is a one-step reaction and avoids the use of organic bases which are difficult to separate.
The process of the present disclosure is simple, employs cost effective and less toxic reagents and provides fluxapyroxad with a comparatively high purity and high yield.
The foregoing description of the embodiments has been provided for purposes of illustration and 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 illustrated herein below with the help of the following experiments. The experiments used herein are intended merely to facilitate an understanding of the 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 experiments should not be construed as limiting the scope of embodiments herein. These laboratory scale experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to industrial/commercial scale.
EXPERIMENTAL DETAILS
Experiment 1: Preparation of 3-(difluoromethyl)-1-methyl-N-(3', 4’, 5’-trifluoro [1, 1’-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (Fluxapyroxad) (I) in accordance with the present disclosure:
A reactor was charged with 10 g of 2-(3,4,5-trifluorophenyl)aniline and 8.9 g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid in 100 ml xylene at 30 °C and stirred for 5 minutes to obtain a first mixture. 9.3 g of phosphorous trichloride was added in a dropwise manner for 10 minutes to the first mixture under stirring at 30 oC to obtain a second mixture. The second mixture was heated to 100 oC and stirred for 5 hours to obtain a product mass comprising 3-(difluoromethyl)-1-methyl-N-(3',4',5'-trifluoro [1,1’-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (Fluxapyroxad). The reaction was monitored by TLC.
The so obtained product mass was cooled to 30 °C, followed by the addition of 50 ml water to obtain a biphasic mixture. The biphasic mixture was stirred for 10 minutes and an organic and an aqueous layer were separated. The organic layer was concentrated to obtain solids of 3-(difluoromethyl)-1-methyl-N-(3', 4’, 5’-trifluoro [1, 1’-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (Fluxapyroxad).
The solids were slurried with 40 ml isopropyl alcohol, filtered and dried to obtain 11 g of 3-(difluoromethyl)-1-methyl-N-(3', 4', 5'-trifluoro [1,1’-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (Fluxapyroxad) with a purity of 99.9%. Yield obtained= 75%.
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 3-(difluoromethyl)-1-methyl-N-(3',4',5'-trifluoro [1,1’-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (Fluxapyroxad), that
• is simple, cost effective and environment friendly;
• provides fluxapyroxad with a comparatively better purity and better yield;
• is a one pot reaction;
• does not employ bases which are difficult to separate;
• employs less toxic and easily available reagents; and
• is commercially scalable.
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 disclosure to achieve one or more of the desired objects or results.
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 mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher/lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to the contrary.
While considerable emphasis has been placed herein on the components and component parts of the preferred embodiments, it will be appreciated that many embodiments can be made and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other changes in the preferred embodiment as well as other embodiments 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 fluxapyroxad, said process comprising the following steps:
i. mixing 2-(3,4,5-trifluorophenyl)aniline and 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid in a first fluid medium at a first predetermined temperature for a first predetermined time period under stirring to obtain a first mixture;
ii. slowly adding a dehydrating agent in said first mixture under stirring at said first predetermined temperature over a second predetermined time period to obtain a second mixture; and
iii. heating said second mixture at a second predetermined temperature and stirred for a third predetermined time period to obtain a product mass comprising fluxapyroxad.

2. The process as claimed in claim 1, wherein said first fluid medium is selected from the group consisting of xylene, toluene, acetonitrile, dichloromethane, ethylene dichloride and chlorobenzene.

3. The process as claimed in claim 1, wherein said first predetermined temperature is in the range of 25 °C to 35 °C.

4. The process as claimed in claim 1, wherein said first predetermined time period is in the range of 2 minutes to 10 minutes.

5. The process as claimed in claim 1, wherein said dehydrating agent is selected from the group consisting of phosphorus trichloride and phosphorus pentoxide.

6. The process as claimed in claim 1, wherein said second predetermined time period is in the range of 2 minutes to 20 minutes.
7. The process as claimed in claim 1, wherein second predetermined temperature is in the range of 80 °C to 125 °C.

8. The process as claimed in claim 1, wherein said third predetermined time period is in the range of 2 hours to 10 hours.

9. The process as claimed in claim 1, wherein a weight ratio of 2-(3,4,5-trifluorophenyl)aniline to 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is in the range of 0.5:1 to 3:1.

10. The process as claimed in claim 1, wherein yield of fluxapyroxad is in the range of 70% to 85% and purity is in the range of 97% to 99.9%.

Dated this 15th day of April, 2024

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

TO,
THE CONTROLLER OF PATENTS
THE PATENT OFFICE, CHENNAI