DESC:FIELD
The present disclosure relates to a process for the synthesis of alkyl thiopyrazoles.

BACKGROUND
Alkyl thiopyrazole, an intermediate of phenylpyrazoles, is used for diverse applications. Alkyl thiopyrazoles have been prolifically used for the synthesis of insecticides. Various processes are known for the synthesis of alkyl thiopyrazoles.

One of the earliest processes involved the condensation of trifluromethanesulfenyl chloride with organomagnesium compounds to obtain pyrazole derivatives.

EP0295117 suggests a two stage process, wherein a thiocyanate pyrazole is formed in the first stage, followed by the reaction of the thiocyanate pyrazole with an alkyl iodide in the second stage to obtain the alkyl thiopyrazole.

Other processes involve the use of catalysts, maintaining reduced pressure, chromatographic separation and such. However, such known processes are accompanied by certain disadvantages such as the use of toxic and/or expensive chemicals, release of harmful effluents, complicated reaction schemes that lead to lengthy reaction time and the like.

Therefore, there is felt a need for a process for synthesizing alkyl thiopyrazoles that is simple, economic, gives a high yield of alkyl thiopyrazoles and is also environmentally safe.

OBJECTS
Some of the objects of the present disclosure which at least one embodiment is adapted to provide, are described herein below:
It is an object of the present disclosure to provide a process for the synthesis of alkyl thiopyrazoles.
It is another object of the present disclosure to provide a process for the synthesis of alkyl thiopyrazoles, which is simple and cost-effective.
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
In accordance with the present disclosure there is provided a process for synthesizing an alkyl thiopyrazole, said process comprises reacting pre-determined quantities of at least one alkyl sulfenyl halide, at least one aminopyrazole, at least one amine salt and at least one solvent, in an inert atmosphere and in the temperature range of -20 to 50°C to obtain the alkyl thiopyrazole. The alkyl sulfenyl halide in accordance with the present disclosure can be pre-formed and introduced into the reaction or can be generated in-situ.

DETAILED DESCRIPTION
The present disclosure provides a process for the synthesis of alkyl thiopyrazoles. The process of the present disclosure comprises steps that include, but are not limited to reacting at least one alkyl sulfenyl halide with at least one aminopyrazole in the presence of at least one amine salt and at least one solvent, in pre-determined proportions. In an embodiment, the afore-stated process is sulfenylation of the aminopyrazole.

The process of the present disclosure is carried out at a pre-determined temperature for a pre-determined time period. In an exemplary embodiment of the present disclosure, the sulfenylation is carried out in the temperature range of -20 to 50°C, with the reaction time ranging from 1 to 8 hours.

In an embodiment of the present disclosure, the process is carried out in an inert atmosphere. The inert atmosphere is maintained using gases such as but not limited to argon and nitrogen.

In an exemplary embodiment of the present disclosure, the alkyl group from the alkyl sulfenyl halide is ethyl and hence, the alkyl sulfenyl halide is ethyl sulfenyl chloride.

The ethyl sulfenyl chloride of the present disclosure is prepared by reacting at least one dialkyl disulfide with a solvent in the temperature range of 25 to 28°C, cooling the solution and then passing chlorine gas to obtain the ethyl sulfenyl chloride.

In an exemplary embodiment of the present disclosure, the dialkyl disulfide is diethyl disulfide.

In an embodiment of the present disclosure the solvent used for preparing the alkyl sulfenyl chloride is selected from ethylene dichloride and methylene dichloride.

In an embodiment of the present disclosure, the alkyl sulfenyl halide is pre-formed and then introduced into the reaction for synthesizing the alkyl thiopyrazole.

In another embodiment of the present disclosure, the alkyl sulfenyl halide is formed in-situ for synthesizing the alkyl thiopyrazole.

The amine salt is formed by complexing at least one amine with at least one aromatic sulfonic acid in the temperature range of 15 to 25°C.

The amine is at least one selected from the group that includes, but is not limited to primary amine, secondary amine, tertiary amine and quaternary amine. In an embodiment of the present disclosure, the amine is at least one selected from the group that includes, but is not limited to dimethyl amine, diethyl amine, isopropyl amine, triethyl amine, morpholine, piperidine, pyrrolidine, imidazole, pyrrole and piperazine.

In another embodiment of the present disclosure, the aromatic sulfonic acid is at least one alkyl substituted aromatic sulfonic acid selected from the group that includes, but is not limited to benzene sulfonic acid and p-toluene sulfonic acid.

In an embodiment of the present disclosure, the amine salt of aromatic sulfonic acid is pre-formed separately and then introduced in the reaction for synthesizing the alkyl thiopyrazole. In accordance with the present disclosure, the amine salt is made moisture-free before being introduced in the reactor for the preparation of the alkyl thiopyrazole.

The solvent used for the preparation of alkyl thiopyrazole in accordance with the present disclosure is at least one selected from the group that includes, but is not limited to an aromatic compound and an aliphatic compound. In a preferred embodiment of the present disclosure the solvent is at least one selected from the group consisting of ethylene dichloride and methylene dichloride.

In one embodiment, the present disclosure provides a process for the preparation of alkyl thiopyrazole by the sulfenylation of at least one pyrazole compound. Typically, the pyrazole compound of the present disclosure is 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonitrile, which is sulfenylated to form alkyl thiopyrazole.

The above constitutes the hitherto unknown sulfenylation process of pyrazole derivatives, which are widely used as intermediates for agrochemicals and more specifically for compounds used as insecticides.

The present disclosure is further described in light of the following non-limiting examples, which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure.

Example 1: Preparation of ethyl thiopyrazole

Example 1A: Preparation of amine salt (p-toluenesulfonic acid dimethylamine salt):

(I): p-toluenesulfonic acid monohydrate powder (190g) was added slowly to an aqueous solution of dimethylamine (10N, 3mole/mole) with maintaining the temperature in the range of 18 to 20°C to get a clear solution. The solution was equilibrated at 25 to 28°C for 1 hour and then dried under vacuum at 100°C till the moisture content of the solid was <0.5%.
(II): 190g of p-toluenesulfonic acid hydrate was dehydrated in toluene at atmospheric pressure till no water was detected in the toluene layer. The clear solution was then cooled to room temperature (25°C). The solid obtained was filtered, washed with toluene and dried till a constant weight was obtained.

Example 1B: Preparation of ethyl sulfenyl chloride
The set up consisted of a reactor equipped with a mechanical stirrer and a water bath with the temperature maintained at 25 to 28°C. Diethyl disulfide (198g, 1.625 moles) was charged into the reactor containing 3.75 liters of ethylene dichloride (EDC) with continuous stirring to obtain a clear pale yellow colored solution. The solution was cooled to 25°C under stirring and then chlorine gas was passed over the solution till a weight gain of 116g was achieved.

Example 1C: Condensation of Ethyl sulfenyl chloride with aminopyrazole
In a second reactor equipped with mechanical stirrer 5-amino-1-[2, 6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonitrile (aminopyrazole) (803 g, 2.5 moles) was charged into 2.5 liters of EDC with continuous stirring to obtain a thin slurry. Next, solid p-toluenesulfonic acid dimethylamine salt (705g, 1.30 mole/mole) obtained in Example 1A (I) was added to the thin slurry with continuous stirring and heated to the temperature of 46°C to obtain a dark brown solution. Then, the ethyl sulfenyl chloride solution obtained in Example 1B was added below the surface of the dark brown solution and the temperature was maintained at 50°C for 6 hours to obtain a dark brown colored clear reaction mixture. The reaction mixture was further maintained at 50°C by Gas Liquid Chromatography (GLC) monitoring. Less than 1% aminopyrazole was detected after 4 hours of maintaining the reaction mixture at 50°C.
The organic layer was concentrated from the reaction mixture under vacuum to obtain 2040 ml/mole of the distillate. 1 liter/mole of toluene was added to the distillate and further concentrated to recover 320 ml/mole of distillate. 1000 ml/mole of water was added to the distillate to obtain a slurry and then cooled to 10°C. The pH of the slurry was adjusted to 7 using sodium carbonate (Na2CO3) and then filtered. The residual cake obtained after filtration was washed twice with chilled toluene (250ml for each washing). Then the residual cake was washed twice with chilled water (500ml for each washing). The residual cake was finally dried till a constant weight was achieved. 826g of ethyl thiopyrazole was obtained: purity by GLC = 99.5%; yield on purity = 86.7%.
Examples 2 to 8:
Examples 2 to 8 were carried out in a process similar to Example 1. The quantities of various reactants used in Examples 2 to 8 are specified in Table-1.

Table-1
Example Amino pyrazole Diethyl disulfide Amine Salt Temperature & Duration Yield Purity
2 161g 40g Pyridine HCl: 75g 45°C-5 hours 192g 99%
3 128g 32g Piperazino ditosylate: 112g 45°C-6 hours - 71%*
4 161g 40g PTSA Pyrrolidine: 171g 45°C-5 hours 175g 96%
5 129g 32g PTSA. Diethylamine: 127g 45°C-7.5 hours 93g 88%
6 160g 40g PTSA piperidine: 167g 45°C-2 hours 169g 99.7%
7 160g 40g PTSA morpholine: 168g 45°C-4 hours 149 g 98.6%
8 161g 41g PTSA imidazole: 156g 45°C-5 hours 149g 98%
PTSA = p- toluenesulfonic acid; *Conversion by GLC only
As illustrated in Table-1, higher yields were obtained when PTSA piperidine and pyridine HCl were used as the amine salt with 99.7% and 99% purity respectively.

Example 9: One pot preparation of ethyl thiopyrazole
1 liter of EDC was charged into a jacketed reactor equipped with a mechanical stirrer and added aminopyrazole (129g, 0.40 mole) into the reactor under continuous stirring to obtain a slurry. p-toluenesulfonic acid dimethylamine salt obtained in Example 1A (II) was added (113g/1.3 mole/mole) to the slurry under continuous stirring, followed by addition of diethyl disulfide (32g, 0.65 mole/mole) to obtain a reaction mass. The reaction mass was cooled to -15°C under stirring and then chlorine gas was charged below the surface of the reaction mass, maintaining the temperature at -18°C. The reaction mass was maintained at -15°C for 1 hour and then the temperature of the reaction mass was raised to 30°C in 4.5 hours. The reaction mass was maintained at 30°C for 2 hours with GLC monitoring. 75% % 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethylthiopyrazole (ethyl thiopyrazole) and 2.5% aminopyrazole was detected.
The organic layer was concentrated under vacuum to obtain 1750 ml/mole of the distillate. 1 liter/mole of toluene was added to the distillate and further concentrated to obtain a reaction mixture in the form of viscous oil which solidified at ambient temperature. 1000 ml/mole of water was added to the reaction mixture to obtain a slurry and the pH of the slurry was adjusted to 7 using sodium carbonate (Na2CO3) and then filtered. The residual cake obtained after filtration was washed twice with chilled toluene (250ml for each washing). Then the residual cake was washed twice with chilled water (500ml for each washing). The residual cake was finally dried till a constant weight was achieved. 145g of ethyl thiopyrazole was obtained: purity = 83%.

TECHNICAL ADVANTAGES AND ECONOMIC SIGNIFICANCE

-The present disclosure provides a simple and safe process for synthesizing alkyl thiopyrazole.
-The present disclosure provides a process for synthesizing alkyl thiopyrazole using inexpensive, readily available and non-toxic reagents.
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the 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 will 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.

Any discussion of documents, acts, materials, devices, articles and 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.

While considerable emphasis has been placed herein on the particular features of this disclosure, it will be appreciated that various modifications 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 modifications in the nature of the disclosure or the preferred embodiments 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:1. A process for synthesizing an alkyl thiopyrazole, said process comprises reacting pre-determined quantities of at least one alkyl sulfenyl halide, at least one aminopyrazole, at least one amine salt and at least one solvent in an inert atmosphere and in the temperature range of -20 to 50°C to obtain the alkyl thiopyrazole.

2. The process as claimed in claim 1, wherein the ratio of said alkyl sulfenyl halide, said aminopyrazole, said amine salt and said solvent is 1.3:1:1.3:2.5.

3. The process as claimed in claim 1, wherein the alkyl group of said alkyl sulfenyl halide is ethyl and the alkyl sulfenyl halide is ethyl sulfenyl chloride.

4. The process as claimed in claim 3, wherein the ethyl sulfenyl chloride is prepared by reacting at least one dialkyl disulfide with at least one solvent in the temperature range of 25 to 28°C to obtain a solution and then passing chlorine gas over the solution.

5. The process as claimed in claim 4, wherein said dialkyl disulfide is diethyl disulfide and said solvent is ethylene dichloride.

6. The process as claimed in claim 1, wherein said amine salt is prepared by reacting at least one amine and at least one aromatic sulfonic acid in the temperature range of 15 to 25°C.

7. The process as claimed in claim 6, wherein said amine is at least one selected from the group consisting of dimethyl amine, diethyl amine, isopropyl amine, triethyl amine, morpholine, piperidine, pyrrolidine, imidazole, pyrrole and piperazine.
8. The process as claimed in claim 6, wherein said aromatic sulfonic acid is at least one selected from the group consisting of benzene sulfonic acid and p-toluene sulfonic acid.

9. The process as claimed in claim 1, wherein said solvent is at least one selected from the group consisting of toluene, ethylene dichloride and methylene dichloride.

10. An alkyl thiopyrazole synthesized in accordance with any of the claims 1 to 9.