DESC:FIELD
The present disclosure relates to a process for the preparation of phenylpyrazole derivatives.
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
Phenylpyrazole derivatives such as Ethiprole, is a non-systemic and broad spectrum phenyl-pyrazole insecticide that is effective against a wide range of insects such as plant hoppers, thrips, aphids, weevils, flies, maggots, grasshoppers, psyllids, leaf miners and some species of whitefly. The structural representation of Ethiprole (i.e. 5-amino-1-[2, 6-dichloro-4-(trifluoromethyl) phenyl]-4-(ethylsulfinyl)-1H-pyrazole-3-carbonitrile) is given as formula (I) below:

(I)
In insects, Ethiprole acts on the ?-aminobutyric acid-dependent neurotransmission present in the central nervous system. It is effective against a broad spectrum of insects with chewing and sucking mouthparts that tend to damage the plants. Ethiprole has a high level of selective toxicity, and thus avoids cross resistance.
Conventional methods for the preparation of phenylpyrazole derivatives provide the product (phenylpyrazole derivative) with impurities. The impurities in phenylpyrazole derivatives may affect the efficacy, safety, and stability of the final product produced by using phenylpyrazole derivatives. The yield/productivity of phenylpyrazole derivatives obtained from the known processes is considerably low. Further, the phenylpyrazole derivative obtained by the conventional processes contains sulfone impurity, which is difficult to separate.
Therefore, there is felt a need to provide a process for the preparation of phenylpyrazole derivatives that mitigates the aforestated drawbacks or at least provides 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 background or to at least provide a useful alternative.
Another object of the present disclosure is to provide a process for the preparation of phenylpyrazole derivatives.
Yet another object of the present disclosure is to provide a process for the preparation of phenylpyrazole derivatives 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 phenylpyrazole derivatives.
Another object of the present disclosure is to provide an environment-friendly and commercially scalable process for the preparation of phenylpyrazole derivatives.
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 phenylpyrazole derivatives. The process comprises reacting sodium sulfide with sulfur to obtain sodium disulfide followed by reacting the sodium disulfide with a compound selected from an alkyl halide and an aryl halide in a first fluid medium in the presence of a first catalyst at a first predetermined temperature for a first predetermined time period to obtain a disulfide compound. The disulfide compound is halogenated with a halogenating agent in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain a sulfenyl halide. The sulfenyl halide is condensed with an amino pyrazole compound in a third fluid medium in the presence of a second catalyst at a third predetermined temperature for a third predetermined time period to obtain a thiopyrazole. The thiopyrazole is oxidized by using an oxidizing agent in a fourth fluid medium in the presence of a third catalyst and an acid at a fourth predetermined temperature for a fourth predetermined time period to obtain the phenylpyrazole derivatives.
In accordance with the present disclosure, the alkyl halide is selected from the group consisting of ethyl chloride, ethyl bromide, methyl chloride, isopropyl chloride, isopropyl bromide, isobutyl chloride and butyl bromide.
In accordance with the present disclosure, the aryl halide is selected from the group consisting of benzyl chloride and benzyl bromide.
In accordance with the present disclosure, the first fluid medium is selected from the group consisting of toluene, cyclohexane, xylene, monochlorobenzene and n-hexane.
In accordance with the present disclosure, the first catalyst is selected from the group consisting of tetrabutylammonium bromide (TBAB), benzyl triethyl ammonium chloride, tetra methyl ammonium chloride and benzyl trimethyl ammonium chloride.
In accordance with the present disclosure, the first predetermined temperature is in the range of 20°C to 40°C; the second predetermined temperature is in the range of 20°C to 30°C; the third predetermined temperature is in the range of 40°C to 55°C; and the fourth predetermined temperature is in the range of 20°C to 35°C.
In accordance with the present disclosure, the first predetermined time period is in the range of 5 hours to 15 hours; the second predetermined time period is in the range of 1 hour to 5 hours; the third predetermined time period is in the range of 5 hours to 15 hours; and the fourth predetermined time period is in the range of 5 hours to 20 hours.
In accordance with the present disclosure, the halogenating agent is chlorine gas.
In accordance with the present disclosure, the second fluid medium is selected from the group consisting of toluene, ethylene dichloride, cyclohexane, xylene, monochloro benzene and n-hexane.
In accordance with the present disclosure, the third fluid medium is selected from the group consisting of ethylene dichloride, toluene, cyclohexane and methylene dichloride.
In accordance with the present disclosure, the second catalyst is selected from the group consisting of alkylamine hydrochloride salt, dialkylamine hydrochloride salt and organic sulfonic acid salt with mono alkyl amine and dialkylformamide.
In accordance with the present disclosure, the second catalyst is diethyl amine hydrochloride salt.
In accordance with the present disclosure, the fourth fluid medium is selected from the group consisting of ethylene dichloride, toluene and cyclohexane.
In accordance with the present disclosure, the oxidizing agent is selected from the group consisting of hydrogen peroxide and m-chloro perbenzoic acid.
In accordance with the present disclosure, the third catalyst is selected from the group consisting of tetrabutyl ammonium bromide (TBAB), benzyl triethyl ammonium chloride, tetra methyl ammonium chloride and benzyl trimethyl ammonium chloride.
In accordance with the present disclosure, the acid is selected from the group consisting of acetic acid and sulphuric acid.
DETAILED DESCRIPTION
The present disclosure relates to a process for the preparation of phenylpyrazole derivatives.
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.
In insects, Ethiprole, a phenylpyrazole derivative acts on the ?-aminobutyric acid-dependent neurotransmission system present in the central nervous system. It is effective against a broad spectrum of insects with chewing and sucking mouthparts that tend to damage the plants. Ethiprole has a high level of selective toxicity, and thus avoids cross resistance.
Conventional methods for the preparation of phenylpyrazole derivatives provide the product (phenylpyrazole derivatives) with impurities. Further, the impurities in phenylpyrazole derivatives may affect the efficacy, safety, and stability of the final product. The yield/productivity of phenylpyrazole derivatives obtained from the known processes is considerably low.
The present disclosure provides an improved process for the preparation of phenylpyrazole derivatives.
The process of the present disclosure is simple, environment friendly, economical, results in improved yield and higher purity of phenylpyrazole derivatives, and is commercially scalable. Further, it is desired that the synthesized phenylpyrazole derivatives contains less than 0.5%, more preferably negligible amount of sulfone impurity.
In an aspect, the present disclosure provides a process for preparing
phenylpyrazole derivatives.
The process for preparing phenylpyrazole derivatives comprises the following steps:
i. reacting sodium sulfide with sulfur to obtain sodium disulfide followed by reacting the sodium disulfide with a compound selected from an alkyl halide and an aryl halide in a first fluid medium in the presence of a first catalyst at a first predetermined temperature for a first predetermined time period to obtain a disulfide compound;
ii. halogenating the disulfide compound with a halogenating agent in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain a sulfenyl halide;
iii. condensing the sulfenyl halide with an amino pyrazole compound in a third fluid medium in the presence of a second catalyst at a third predetermined temperature for a third predetermined time period to obtain a thiopyrazole; and
iv. oxidizing the thiopyrazole by using an oxidizing agent in a fourth fluid medium in the presence of a third catalyst and an acid at a fourth predetermined temperature for a fourth predetermined time period to obtain the phenylpyrazole derivatives.
The process for preparing the phenylpyrazole derivatives in accordance with the present disclosure is described in detail herein below.
Step I: Preparation of a disulfide compound
In a first step, a predetermined amount of sodium sulfide is reacted with predetermined amount of sulfur to obtain sodium disulfide. The so obtained sodium disulfide is reacted with a compound selected from an alkyl halide and an aryl halide in a first fluid medium in the presence of a first catalyst at a first predetermined temperature for a first predetermined time period to obtain a disulfide compound.
The step for the preparation of disulfide compounds is given in detail below:
In accordance with the present disclosure, a predetermined amount of sodium sulfide is dissolved in water, followed by adding a predetermined amount of sulfur powder at a temperature in the range of 40 °C to 60 °C for a time period in the range of 1 hour to 3 hours under stirring to obtain a first solution. The first solution is cooled to a temperature in the range of 20 °C to 40 °C to obtain a cooled solution comprising sodium disulfide. In an exemplary embodiment, the sodium sulfide is dissolved in water, followed by adding a predetermined amount of sulfur powder at 50 °C for 2 hours to obtain a first solution. The first solution is cooled to 30 °C to obtain a cooled solution comprising sodium disulfide.
A predetermined amount of the so obtained cooled solution comprising sodium disulfide (without isolation/purification) is mixed with a first fluid medium followed by adding a predetermined amount of a first catalyst to obtain a first mixture. A compound selected from an alkyl halide and an aryl halide is slowly added to the first mixture at a first predetermined temperature for a time period in the range of 4 hours to 7 hours to obtain a second mixture. The second mixture is stirred at the first predetermined temperature for a time period in the range of 1 hour to 3 hours to obtain a product mixture comprising disulfide compound. The reaction progress is monitored by gas liquid chromatography (GLC).
The alkyl halide is selected from the group consisting of ethyl chloride, ethyl bromide, methyl chloride, isopropyl chloride, isopropyl bromide, isobutyl chloride and butyl bromide. In an exemplary embodiment of the present disclosure, alkyl halide compound is ethyl chloride.
The aryl halide is selected from the group consisting of benzyl chloride and benzyl bromide.
In an embodiment of the present disclosure, the first fluid medium is selected from the group consisting of toluene, cyclohexane, xylene, monochlorobenzene and hexane. In an exemplary embodiment of the present disclosure, the first fluid medium is toluene.
The first catalyst is selected from the group consisting of tetrabutyl ammonium bromide (TBAB), benzyl triethyl ammonium chloride, tetra methyl ammonium chloride and benzyl trimethyl ammonium chloride. In an exemplary embodiment of the present disclosure, the first catalyst is tetrabutyl ammonium bromide.
In an embodiment of the present disclosure, the first predetermined temperature is in the range of 20°C to 40°C. In an exemplary embodiment of the present disclosure, the first predetermined temperature is 25 °C.
In an embodiment of the present disclosure, the first predetermined time period is in the range of 5 hours to 15 hours. In an exemplary embodiment of the present disclosure, the first predetermined time period is 7 hours.
In an embodiment of the present disclosure, the first predetermined time period is a combined time period of slow addition of alkyl/aryl halide to the first mixture and their stirring time period.
The product mixture is settled to separate out a first organic layer and a first aqueous layer. The so obtained first aqueous layer is mixed with the first fluid medium, followed by separation to obtain a second organic layer and a second aqueous layer. The first organic layer and the second organic layer are mixed, followed by washing with water to obtain a resultant organic layer. The resultant organic layer is subjected to vacuum distillation to remove the first fluid medium to obtain the disulfide compound.
In an embodiment of the present disclosure, the disulfide compound is selected from dialkyl disulfide compound and diaryl disulfide compound.
In an embodiment of the present disclosure, the dialkyl disulfide compounds are selected from the group consisting of diethyl disulfide, dimethyl disulfide, diisopropyl disulfide, and dibutyl disulfide. In an exemplary embodiment of the present disclosure, the dialkyl disulfide compound is diethyl disulfide.
In an embodiment of the present disclosure, the diaryl disulfide compound is dibenzyl disulfide.
In an embodiment of the present disclosure, the disulfide compounds have purity (GLC purity) in the range of 98 % to 99.5 %. In an exemplary embodiment, the purity (GLC purity) of diethyl disulfide is 99.0 %.
In an embodiment of the present disclosure, the yield of the disulfide compounds is in the range of 90 % to 95 %. In an exemplary embodiment, the yield of diethyl disulfide is 92.0 %.
In an exemplary embodiment of the present disclosure, a schematic representation for the preparation of diethyl disulfide is given as scheme A below.

Scheme A
Step II: Preparation of a sulfenyl halide
In a second step, the disulfide compound is halogenated with a halogenating agent in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain a sulfenyl halide.
The step for the preparation of sulfenyl halide is given in detail below:
A predetermined amount of disulfide compound is dissolved in a second fluid medium to obtain a solution. The solution is cooled to a second predetermined temperature to obtain a cooled solution. Halogenating agent is slowly added to the cooled solution over a time period in the range of 1 hour to 3 hours and stirred at a time period in the range of 20 minutes to 60 minutes to obtain a clear solution comprising sulfenyl halide.
In an embodiment of the present disclosure, the halogenating agent is chlorine gas.
In an embodiment of the present disclosure, the second fluid medium is selected from the group consisting of ethylene dichloride, toluene, cyclohexane, xylene, monochloro benzene and n-Hexane. In an exemplary embodiment of the present disclosure, the second fluid medium is ethylene dichloride.
In an embodiment of the present disclosure, the second predetermined temperature is in the range of 20 °C to 30 °C. In an exemplary embodiment of the present disclosure, the second predetermined temperature is 25 °C.
In an embodiment of the present disclosure, the second predetermined time period is in the range of 1 hour to 5 hours. In an exemplary embodiment of the present disclosure, the second predetermined time period is 2.5 hours.
In an embodiment of the present disclosure, the second predetermined time period is a combined time period of slow addition of chlorine to the cooled solution and their stirring time period.
In an embodiment of the present disclosure, the sulfenyl halide is selected from the group consisting of alkyl sulfenyl halide and aryl sulfenyl halide.
In an embodiment of the present disclosure, the alkyl sulfenyl halide is selected from the group consisting of ethyl sulfenyl chloride, methyl sulfenyl chloride, isopropyl sulfenyl chloride, butyl sulfenyl chloride, benzyl sulfenyl chloride, ethyl sulfenyl bromide, methyl sulfenyl bromide, isopropyl sulfenyl bromide, butyl sulfenyl bromide, ethyl sulfenyl iodide, methyl sulfenyl iodide, isopropyl sulfenyl iodide, and butyl sulfenyl iodide. In an exemplary embodiment of the present disclosure, the alkyl sulfenyl halide is ethyl sulfenyl chloride.
In an embodiment of the present disclosure, the aryl sulfenyl halide is selected from the group consisting of benzyl sulfenyl bromide, benzyl sulfenyl iodide and benzyl sulfenyl chloride.
In an exemplary embodiment of the present disclosure, a schematic representation for the preparation of ethyl sulfenyl chloride is given as scheme B below.

Scheme B
Step III: Preparation of a thiopyrazole
In a third step, the so obtained sulfenyl halide is condensed with an amino pyrazole compound in a third fluid medium in the presence of a second catalyst at a third predetermined temperature for a third predetermined time period to obtain a thiopyrazole.
The step for the preparation of the thiopyrazole is given in detail below:
In this step, a predetermined amount of an amino pyrazole is dissolved in a third fluid medium to obtain a first clear solution. A predetermined amount of a second catalyst is added to the first clear solution and heated to a third predetermined temperature to obtain a second solution. A predetermined amount of the sulfenyl halide is slowly added to the second solution at a third predetermined temperature for a time period in the range of 5 hours to 7 hours to obtain a reaction mixture. The reaction mixture is stirred at the third predetermined temperature for a time period in the range of 3 hours to 5 hours to obtain a product mixture comprising a thiopyrazole. The reaction progress is monitored by HPLC.
After completion of the reaction, the product thiopyrazole is isolated by using the first fluid medium and water followed by filtration to obtain a first wet cake. The first wet cake is washed with the first fluid medium followed by water to obtain a second wet cake. The second wet cake is dried in an oven at a temperature in the range of 50 °C to 70 °C to obtain a dried thiopyrazole compound.
In an exemplary embodiment of the present disclosure, the amino pyrazole compound is 5-amino-1-[2, 6-dichloro-4-(trifluoromethylphenyl)-3-cyanopyrazole.
The third fluid medium is selected from the group consisting of ethylene dichloride, toluene, cyclohexane and methylene dichloride. In an exemplary embodiment of the present disclosure, the third fluid medium is ethylene dichloride.
The second catalyst is selected from the group consisting of alkylamine hydrochloride salt, dialkylamine hydrochloride salt and organic sulfonic acid salt with mono alkyl amine and dialkylformamide. In an exemplary embodiment of the present disclosure, the second catalyst is diethylamine hydrochloride salt.
The third predetermined temperature is in the range of 40 °C to 55 °C. In an exemplary embodiment of the present disclosure, the third predetermined temperature is 45 °C.
The third predetermined time period is in the range of 5 hours to 15 hours. In an exemplary embodiment of the present disclosure, the third predetermined time period is 10 hours.
In an embodiment of the present disclosure, the third predetermined time period is a combined time period of slow addition of sulfenyl halide to the second solution and their stirring time period.
In an embodiment of the present disclosure, the thiopyrazole is alkyl thiopyrazole. The alkyl thiopyrazole is selected from the group consisting of ethyl thiopyrazole, methyl thiopyrazole, isopropyl thiopyrazole and butyl thiopyrazole. In an exemplary embodiment of the present disclosure, the alkyl thiopyrazole is ethyl thiopyrazole.
In another embodiment of the present disclosure, the thiopyrazole is aryl thiopyrazole. The aryl thiopyrazole is benzyl thiopyrazole.
In an embodiment of the present disclosure, the alkyl thiopyrazole has purity (HPLC purity) in the range of 95% to 99.9 %. In an exemplary embodiment of the present disclosure, the purity of alkyl thiopyrazole is 99%.
In an embodiment of the present disclosure, the yield of the alkyl thiopyrazole is in the range of 85% to 95%. In an exemplary embodiment of the present disclosure, the yield of alkyl thiopyrazole is 92%.
In an embodiment of the present disclosure, the aryl thiopyrazole has a purity (HPLC purity) in the range of 98.5% to 99.25%.
In an embodiment of the present disclosure, the yield of the aryl thiopyrazole is in the range of 90% to 93%.
In an exemplary embodiment of the present disclosure, a schematic representation for the preparation of ethyl thiopyrazole is given as scheme C below.

Scheme C

Step IV: Preparation of phenylpyrazole derivative by using the thiopyrazole
In a fourth step, the so obtained thiopyrazole is oxidized by using an oxidizing agent in a fourth fluid medium in the presence of a third catalyst and an acid at a fourth predetermined temperature for a fourth predetermined time period to obtain a phenylpyrazole derivative.
The step for the preparation of the phenylpyrazole derivative is given in detail below:
In this step, a predetermined amount of the so obtained thiopyrazole is mixed with a fourth fluid medium under stirring for a time period in the range of 10 minutes to 20 minutes to obtain a first mixture. The first mixture is reacted with a predetermined amount of an acid and a third catalyst at a fourth predetermined temperature for a time period in the range of 20 minutes to 40 minutes under stirring to obtain a second mixture. A predetermined amount of an oxidizing agent is slowly added to the second mixture over a time period in the range of 4 hours to 10 hours at a fourth predetermined temperature followed by stirring for a time period in the range of 4 hours to 8 hours to obtain a product mixture comprising phenyl pyrazole derivatives. The reaction progress is monitored by HPLC.
After completion of the reaction, the product mixture is cooled at a temperature in the range of 20 °C to 30 °C for a time period in the range of 20 minutes to 40 minutes to obtain a first wet cake. The first wet cake is washed with fourth fluid medium and dried to obtain a second wet cake. The second wet cake is reslurried in water and stirred for a time period in the range of 0.5 hours to 2 hours to obtain a third wet cake. The third wet cake is washed with 5% sodium bicarbonate solution so that the pH of the filtrate is 7 followed by washing with water to obtain a fourth wet cake. The fourth wet cake is dried to obtain a crude phenylpyrazole derivative.
The oxidizing agent is selected from the group consisting of hydrogen peroxide and m-chloro perbenzoic acid. In an exemplary embodiment of the present disclosure, the oxidizing agent is hydrogen peroxide.
The third catalyst is selected from the group consisting of tetrabutyl ammonium bromide (TBAB), benzyl triethyl ammonium chloride, tetra methyl ammonium chloride and benzyl trimethyl ammonium chloride. In an exemplary embodiment of the present disclosure, the third catalyst is benzyl triethyl ammonium chloride.
The acid is selected from the group consisting of acetic acid and sulphuric acid. In an exemplary embodiment of the present disclosure, the acid is acetic acid.
The fourth fluid medium is selected from the group consisting of ethylene dichloride, toluene and cyclohexane. In an exemplary embodiment of the present disclosure, the fourth fluid medium is ethylene dichloride.
The fourth predetermined temperature is in the range of 20 °C to 35 °C. In an exemplary embodiment of the present disclosure, the fourth predetermined temperature is 30 °C.
The fourth predetermined time period is in the range of 5 hours to 20 hours. In an exemplary embodiment of the present disclosure, the fourth predetermined time period is 12 hours.
In an embodiment of the present disclosure, the fourth predetermined time period is a combined time period of slow addition of oxidizing agent to the second mixture and their stirring time period.
In an embodiment of the present disclosure, the phenylpyrazole derivative is selected from the group consisting of alkyl phenylpyrazole derivative and aryl phenylpyrazole derivative. In an exemplary embodiment, the alkyl phenylpyrazole derivative is Ethiprole.
In an embodiment of the present disclosure, the crude phenylpyrazole derivative has a purity (HPLC purity) in the range of 82 % to 84 %.
In an exemplary embodiment of the present disclosure, a schematic representation for the preparation of Ethiprole compound is given as scheme D.

Scheme D
Purification of the crude product of phenylpyrazole derivative
The crude phenylpyrazole derivative obtained in step-IV is mixed in a solvent and heated to a temperature in the range of 80°C to 90°C and is stirred at 80°C to 90°C for a time period in the range of 1 hour to 3 hours to obtain a slurry. The slurry is cooled at a temperature in the range of 50 °C to 70 °C and filtered to obtain a cake. The cake is washed with a solvent, followed by drying in an oven at a temperature in the range of 65 °C to 75 °C for 5 to 7 hours to obtain a purified product of phenylpyrazole derivative.
In an embodiment of the present disclosure, the solvent is selected from the group consisting of ethylene dichloride and methylene dichloride. In an exemplary embodiment of the present disclosure, the solvent is ethylene dichloride.
In an embodiment of the present disclosure, the pure phenylpyrazole derivative have a purity (HPLC purity) in the range of 96 % to 97 %.
In an embodiment of the present disclosure, the yield of the pure phenylpyrazole derivative is in the range of 80% to 85%.
The present disclosure provides a simple and economic process for the preparation of phenylpyrazole derivatives with a comparatively higher yield and better purity.
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 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 can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to the industrial scale.
EXPERIMENTAL DETAILS:
EXAMPLE 1: PREPARATION OF ETHIPROLE
Step I: Preparation of diethyl disulphide
Preparation of Na2S2
265 gm of sodium sulfide was dissolved in 400 ml of water followed by adding 32 gm of sulfur powder under stirring and heated to 50°C and further stirred for 2 hours to obtain a first solution. The first solution was cooled to 30°C to obtain a cooled solution comprising sodium disulfide.
Preparation of disulfide compound (diethyl disulfide)
To the 697 gm of cooled solution comprising sodium disulfide, 300 ml of toluene, 6.44 gm of Tetrabutylammonium bromide (TBAB) was mixed to obtain a first mixture.
129 gm of ethyl chloride gas was slowly passed to the first mixture at 25°C for 5 hours to obtain a second mixture. The second mixture was further stirred at 25°C for 2 hours to obtain a product mixture comprising diethyl disulfide compound. GLC of the organic layer was checked.
After complete conversion, the product mixture was settled to separate out a first toluene layer and a first aqueous layer. The first aqueous layer was separated to obtain a separated first toluene layer and a separated first aqueous layer. 100 ml of toluene was added in the separated first aqueous layer, followed by separation to obtain a separated second toluene layer and a separated second aqueous layer. The separated first toluene layer and the separated second toluene layer were mixed, followed by washing with 100 ml of water to obtain a resultant organic layer. The resultant organic layer was subjected to vacuum distillation to remove toluene to obtain the diethyl disulfide compound.
The weight of diethyl disulfide obtained was 110gm.
The purity of the diethyl disulfide obtained was 99.0%.
The yield of diethyl disulfide 92%.
Step II: Preparation of ethyl sulfenyl chloride
77.5 gm of diethyl disulfide obtained in Step I was dissolved in 2300 ml of ethylene dichloride to obtain a solution. The solution was cooled to 25°C to obtain a cooled solution. To the obtained cooled solution 46 gm of chlorine gas was slowly passed under stirring over 2 hours and further stirred for 30 minutes to obtain a clear solution comprising ethyl sulfenyl chloride.
Step-III: Preparation of ethyl thiopyrazole:
321 gm of 5-amino-1-[2, 6-dichloro-4-(trifluoromethylphenyl)-3-cyanopyrazole and 1000 ml of ethylene dichloride were stirred to obtain a first clear solution. 281 gm of diethyl amine hydrochloride salt was added to the first clear solution and heated at 45°C to obtain a second solution. 2400 ml of ethyl sulfenyl chloride obtained in step-II was slowly added to a second solution at 45°C for 6 hours to obtain a reaction mixture. The reaction mixture was stirred at 45°C for 4 hours to obtain a product mixture comprising ethyl thiopyrazole. The reaction was monitored by HPLC.
After completion of the reaction, the product mixture was concentrated at 50°C under vacuum to obtain a first slurry. 1000 ml of toluene was added to the first slurry and stirred for 30 minutes to obtain a second slurry. Toluene and ethylene dichloride was distilled from the second slurry under vacuum to obtain a mass. To the obtained mass 1000ml of water was added and the mass was cooled to 10°C and filtered to obtain a first wet cake. The first wet cake was washed with 200 ml cold toluene twice followed by washing with 250 ml of water to obtain a second wet cake. The second wet cake was dried in an oven at 60 °C to obtain a dried ethyl thiopyrazole compound.
The weight of ethyl thiopyrazole obtained was 355 gm.
The purity of ethyl thiopyrazole obtained was 99.0%.
The yield of ethyl thiopyrazole was 92%.
Step-IV: Preparation of Ethiprole:
381 gm of the so obtained dried ethyl thiopyrazole was mixed with 1500 ml of ethylene dichloride under stirring for 15 minutes to obtain a first mixture. To the so obtained first mixture 120 gm of acetic acid, 4 gm of benzyl triethyl ammonium chloride were added under stirring for 30 minutes at 30°C to obtain a second mixture. 82 gm of hydrogen peroxide was slowly added at 30°C over 6 hours followed by stirring for another 6 hours to obtain a product mixture comprising ethiprole. The reaction was monitored by HPLC. HPLC results are summarized in table 1 below:
Table 1:HPLC results of product mixture comprising ethiprole
Ethiprole Sulfone Ethyl Thiopyrazole Impurity
80-83% 0.4-0.7% 15-18% <0.1%

After completion of the reaction, the product mixture was cooled to 25°C and stirred for 30 minutes to obtain a first wet cake. The obtained wet cake was washed with 250 ml of ethylene dichloride and dried to obtain a second wet cake. The second wet cake was reslurried in 500 ml of water and stirred for 1 hour to obtain a third wet cake. The third wet cake was washed with 150 ml. of 5% NaHCO3 solution so that the pH of the filtrate was 7 followed by washing with water to obtain a fourth wet cake. The fourth wet cake was dried in an oven to obtain a crude ethiprole.
Dry weight of the crude ethiprole was 305gm. HPLC results of crude ethiprole are summarized in table 2 below:
Table 2:HPLC results of crude ethiprole
Ethiprole Sulfone Ethyl Thiopyrazole Impurity
82-84% 0.3-0.5% 15-17% <0.1%

Example 2: Purification of the crude Ethiprole:
305 gm of the crude Ethiprole obtained in example 1 was mixed with 915 ml ethylene dichloride and heated to 85°C under stirring for 2 hours to obtain a slurry. The slurry was cooled to 60 °C and filtered to obtain a cake. The cake was washed with ethylene dichloride, followed by drying in an oven at 70 °C for 6 hours to obtain a pure ethiprole.
Dry weight of pure ethiprole = 220-230 gm. Yield of Ethiprole = 55-60%.
HPLC results of purified ethiprole are summarized in table 3 below:
Table 3: HPLC results of purified ethiprole
Ethiprole Sulfone Ethyl Thiopyrazole Impurity
97-97.5% 0.30% 2.0-2.25% Nil

Comparative Example 1:
HPLC of Ethiprole obtained by the conventional processes shows following results:
Table 4: HPLC results of ethiprole obtained by conventional process
Ethiprole Sulfone Ethyl Thiopyrazole Other Impurities
95-96% 1.5% 2.0-3.25% <0.1%

The sulfone impurity obtained by the conventional process during preparation of Ethiprole is 1.5%. From table 3 of example 2 above, wherein Ethiprole was prepared in accordance with the process of the present disclosure, it was seen that the sulfone impurity was reduced to 0.30%. Therefore, the process of the present disclosure is efficient for obtaining reduced amount of sulfone impurities (upto 0.3%) in the final product (i.e., phenylpyrazole) thereby resulting in a more effective product.
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 phenylpyrazole derivatives that;
• enables to recover fluid medium, hence economical;
• is simple and environment friendly;
• provides phenylpyrazole derivatives having a comparatively high purity and in high yield; and
• reduces the sulfone impurity
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 preparing phenylpyrazole derivatives, said process comprising the following steps:
i. reacting sodium sulfide with sulfur to obtain sodium disulfide followed by reacting the sodium disulfide with a compound selected from an alkyl halide and an aryl halide in a first fluid medium in the presence of a first catalyst at a first predetermined temperature for a first predetermined time period to obtain a disulfide compound;
ii. halogenating said disulfide compound with a halogenating agent in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain a sulfenyl halide;
iii. condensing said sulfenyl halide with an amino pyrazole compound in a third fluid medium in the presence of a second catalyst at a third predetermined temperature for a third predetermined time period to obtain a thiopyrazole; and
iv. oxidizing said thiopyrazole by using an oxidizing agent in a fourth fluid medium in the presence of a third catalyst and an acid at a fourth predetermined temperature for a fourth predetermined time period to obtain the phenylpyrazole derivatives.

2. The process as claimed in claim 1, wherein said alkyl halide is selected from the group consisting of ethyl chloride, ethyl bromide, methyl chloride, isopropyl chloride, isopropyl bromide, isobutyl chloride and butyl bromide.

3. The process as claimed in claim 1, wherein said aryl halide is selected from the group consisting of benzyl chloride and benzyl bromide.

4. The process as claimed in claim 1, wherein said first fluid medium is selected from the group consisting of toluene, cyclohexane, xylene, monochlorobenzene and n-hexane.

5. The process as claimed in claim 1, wherein said first catalyst is selected from the group consisting of tetrabutylammonium bromide (TBAB), benzyl triethyl ammonium chloride, tetra methyl ammonium chloride and benzyl trimethyl ammonium chloride.

6. The process as claimed in claim 1, wherein said first predetermined temperature is in the range of 20°C to 40°C; said second predetermined temperature is in the range of 20°C to 30°C; said third predetermined temperature is in the range of 40°C to 55°C; and said fourth predetermined temperature is in the range of 20°C to 35°C.

7. The process as claimed in claim 1, wherein said first predetermined time period is in the range of 5 hours to 15 hours; said second predetermined time period is in the range of 1 hour to 5 hours; said third predetermined time period is in the range of 5 hours to 15 hours; and said fourth predetermined time period is in the range of 5 hours to 20 hours.

8. The process as claimed in claim 1, wherein said halogenating agent is chlorine gas.

9. The process as claimed in claim 1, wherein said second fluid medium is selected from the group consisting of toluene, ethylene dichloride, cyclohexane, xylene, monochloro benzene and n-hexane.

10. The process as claimed in claim 1, wherein said third fluid medium is selected from the group consisting of ethylene dichloride, toluene, cyclohexane and methylene dichloride.

11. The process as claimed in claim 1, wherein said second catalyst is selected from the group consisting of alkylamine hydrochloride salt, dialkylamine hydrochloride salt and organic sulfonic acid salt with mono alkyl amine and dialkylformamide.

12. The process as claimed in claim 1, wherein said second catalyst is diethyl amine hydrochloride salt.

13. The process as claimed in claim 1, wherein said fourth fluid medium is selected from the group consisting of ethylene dichloride, toluene and cyclohexane.

14. The process as claimed in claim 1, wherein said oxidizing agent is selected from the group consisting of hydrogen peroxide and m-chloro perbenzoic acid.

15. The process as claimed in claim 1, wherein said third catalyst is selected from the group consisting of tetrabutyl ammonium bromide (TBAB), benzyl triethyl ammonium chloride, tetra methyl ammonium chloride and benzyl trimethyl ammonium chloride.

16. The process as claimed in claim 1, wherein said acid is selected from the group consisting of acetic acid and sulphuric acid.

Dated this 30th day of November, 2023

_______________________________
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