DESC:FORM – 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2006

COMPLETE SPECIFICATION
(See Section 10; Rule 13)

A PROCESS FOR PREPARING AMINO PYRAZOLE DERIVATIVE

GHARDA CHEMICALS LTD.
an Indian company
of B-27/29, MIDC Dombivli (East),
Thane – 421203, Maharashtra, India

Inventors:

1. MATHUR SUCHET S.
2. MALWANKAR JAGADISH R.
3. SANE VIJAY Y.
4. PEDVI VISHAL P.
5. MHATRE HRIDAYNATH V.

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF DISCLOSURE
The present disclosure relates to a process for preparing an amino-pyrazole derivative. Particularly, the present disclosure relates to a process for preparing a substituted amino-pyrazole derivative.

BACKGROUND
Fipronil is a pesticide characterized by high efficiency, low toxicity and low residue. Chemical name of Fipronil is 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole. An important intermediate in the preparation of Fipronil is 5-amino-3-cyano-1-(2,6-dichloro-4-triflouromethylphenyl)pyrazole. This substituted amino-pyrazole derivative can be synthesized from the corresponding substituted aniline via its conversion to diazonium salt followed by reaction with an alkyl 2,3-dicyanopropionoate to get an intermediate which further reacts in the presence of ammonia to form pyrazole ring.
WO2011107998 discloses synthesis of Fipronil (I) via intermediate 2,6-dichloro-4-trifluormethylaniline (V), as shown in scheme 1.

The synthesis disclosed in WO2011107998 includes a step of diazotizing aniline compound of formula V (2,6-dichloro-4-trifluormethylaniline) with nitrosyl sulphate in the presence of acetic acid to form a diazo compound. This step is carried out in the presence of large amount of acetic acid. Higher volume of reaction mixture decreases effective utilization of the reaction vessel. Further, use of acetic acid makes this step less economical as recovery of acetic acid is poor and energy intensive process. Thus, the process disclosed in WO2011107998 needs more energy and is costly.
Thus, there is felt a need to provide a process for the preparation of amino pyrazole derivative that is energy efficient and economical.

OBJECTS
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 provide a process for preparing substitued amino-pyrazole derivative from substituted aniline that is energy efficient.
It is another object of the present disclosure to provide a process for preparing substituted amino-pyrazole derivative from substituted aniline that is economical.
Other objects and advantages of the present disclosure will be more apparent from the following description when read in conjunction with the accompanying figures, which are not intended to limit the scope of the present disclosure.

SUMMARY
In the process described in the present disclosure, diazotization of 2,6-dichloro-4-trifluormethylaniline is carried out without using acetic acid. 2,6-Dichloro-4-trifluormethylaniline is reacted with nitrosyl sulfate to obtain a diazo compound. The diazotization reaction can be carried out in the presence of sulfuric acid. The diazo compound is reacted with alkyl 2,3-dicyanopropionate to get an intermediate. The intermediate is further added to an ammonia solution to obtain a reaction mass which is maintained at a pH in the range of 7 to 12. Ammonia is removed from the reaction mass and precipitate is filtered to get substituted amino-pyrazole derivative. The overall process is energy efficient and economical.

DETAILED DESCRIPTION
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 description herein after, 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 below.

In the process disclosed in WO2011107998 for the preparation of substituted amino-pyrazole derivative, the diazotization of 2,6-dichloro-4-trifluormethylaniline is carried out in the presence of acetic acid. The use of acetic acid makes the overall process expensive and energy intensive. In order to overcome the aforesaid disadvantages, the present disclosure focuses on the preparation of substituted amino-pyrazole derivative from substituted aniline without the use of acetic acid in the diazotization step. The disclosed process is described herein below.
The substituted aniline employed in the present process includes but is not limited to 2,6-dichloro-4-trifluoromethylaniline and the substituted amino-pyrazole derivative includes but is not limited to 5-amino-3-cyano-1-(2,6-dichloro-4-triflouromethylphenyl)pyrazole.
In accordance with the present disclosure, the process for preparing substituted amino-pyrazole derivative from substituted aniline involves three steps.
In the first step, substituted aniline is diazotized with a diazotization reagent to form a diazo compound.
The diazotization reagent is selected from a group consisting of nitrosyl sulphate and sodium nitrite.
In preferred embodiment of the present disclosure the diazotization reagent is nitrosyl sulphate.
The molar ratio of the substituted aniline to the diazotization reagent ranges from 1:1 to 1:1.5.
In preferred embodiment of the present disclosure the molar ratio of the substituted aniline to the diazotization reagent is 1:1.3.
In accordance with another embodiment of the present disclosure the diazotization step is carried out in the presence of H2SO4. The concentration of sulfuric acid ranges from 60 to 90%.
The diazotization reaction is carried out at a temperature ranging from 30°C to 60°C.
In the second step, the diazo compound is reacted with an alkyl 2,3-dicyanopropionate to obtain an intermediate.
Alkyl 2,3-dicyanopropionate is selected from a group consisting of methyl 2,3-dicyanopropionate and ethyl 2,3-dicyanopropionate.
In preferred embodiment of the present disclosure alkyl 2,3-dicyanopropionate is ethyl 2,3-dicyanopropionate.
The molar ratio of the substituted aniline to alkyl 2,3-dicyanopropionate ranges from 1:0.95 to 1:1.5.
In preferred embodiment of the present disclosure the molar ratio of the substituted aniline to alkyl 2,3-dicyanopropionate is 1:1.05.
The solvent used for second step is at least one solvent selected from the group consisting of toluene and ethylene dichloride.
In preferred embodiment of the present disclosure the second step is carried out in toluene.
The second step is carried out at a temperature ranging from 10°C to 50°C.
The third step involves adding the intermediate to an ammonia solution to obtain a reaction mass, maintaining the mass at a pH ranging from 7 to 12, removing ammonia and filtering to obtain the substituted amino-pyrazole derivative.
The concentration of ammonia solution ranges from 10N to 13N.
The reaction of the intermediate with ammonia solution is carried out at a temperature ranging from -5°C to 10°C.
The disclosure is further illustrated with the help of following examples which should not be construed to limit the disclosure.
Example-1
1.0 mol of 2,6-Dichloro-4-trifluoromethylaniline (DCTFMA) was dissolved in 180g of 60% H2SO4 at 50°C, the reaction mixture was cooled and 1.3 mol of nitrosyl sulfate was added over 1.5hrs. The mixture was stirred at 45-50°C till TLC indicated complete consumption of DCTFMA (5hrs). Excess nitrosyl sulfate was destroyed using urea.
A solvent mixture containing 500ml toluene and 1.9L of water was added at 10°C to the diazo mass formed above. 1.05 mol of ethyl 2,3-dicyanopropionate (DCEP) was added at 25-30°C over a period of 1.5 hrs to the reaction mixture followed by stirring at 25-30°C for 10hrs. The organic layer was separated and the aqueous layer was extracted with toluene. The combined organic layer was washed with water and charged to 600ml of concentrated ammonia solution at a temperature less than 5°C over a period of 2hrs. The reaction was maintained at 0-5°C for 7 hrs. Ammonia was bubbled to maintain the pH of the mixture above 7. Upon complete consumption of the coupled mass as monitored by TLC, excess NH3 was removed by applying vacuum till 40°C and the product was filtered to yield 295g amino-pyrazole derivative (>80%) having a purity of >90%.
Example-2
1.3 mol of Nitrosyl sulfate was added to 1.0 mol 2,6-dichloro-4-trifluoromethylaniline (DCTFMA) at 40-450C. The reaction mass was maintained at 45-500C till TLC indicated complete conversion of DCTFMA (5hrs). Excess nitrosyl sulfate was destroyed using urea.
500ml Toluene and 1560ml water was added to the diazo mass at 100C. 1.05 mole of ethyl 2,3-dicyanopropionate (DCEP) was then charged to the reaction mass over a period of 1hr at 25-30°C and the reaction mass was stirred at 25-300C for 8hrs to obtain a product mixture. The organic layer was separated and the aqueous layer was extracted with toluene. The combined organic layer was added to 600 ml of concentrated ammonia solution at a temperature below 5°C over a period of 2hrs. Ammonia was bubbled to maintain the pH of the mixture above 7 and reaction was maintained at 0-5°C till TLC showed consumption of coupled mass (7hrs). Excess NH3 was removed by applying vacuum till 40°C and the product was filtered to yield 303g amino pyrazole derivative (>80%) having a purity of >90 %.
Example-3
1.3 mol of Nitrosyl sulfate was added to 1.0 mol of 2,6-dichloro-4-trifluoromethyl aniline (DCTFMA) at 40-450C and the reaction mass was maintained at 45-500C till complete conversion of DCTFMA (5 hrs) to obtain diazo mass. Excess nitrosyl sulfate was destroyed using urea and a mixture containing 500ml toluene & 1000ml water was added to the diazo mass at 100C followed by addition of 1.05 mole of ethyl 2,3-dicyanopropionate (DCEP) over a period of 1hr at 25-30°C and the reaction mass was stirred at 25-300C for 8hrs to obtain a product mixture. The organic layer was separated and the aqueous layer was extracted with toluene. The combined organic layer was added to 600ml of concentrated ammonia solution below 5°C over a period 2 hrs. Ammonia was bubbled to maintain the pH of the mixture above 7 and reaction was maintained at 0-5°C till TLC showed consumption of the coupled mass (7hrs). Excess NH3 was removed by applying vacuum till 40°C and the product obtained was filtered to yield 255g amino-pyrazole derivative (>60%) having a purity of >85%.
Example-4
1.3 mol of Nitrosyl sulfate was added to 1.0 mol 2,6-dichloro-4-trifluoromethyl aniline (DCTFMA) at 40-450C and the reaction mass was maintained at 45-500C for 5hrs till complete consumption of DCTFMA to obtain diazo mass. Excess nitrosyl sulfate was destroyed using urea and the reaction mass was cooled to 5°C. Sulphuric acid in the reacted mass was neutralized with 2.3N ammonia to adjust strength to 21%. 500 ml toluene was then added to diazo mass followed by addition 1.05 mole of ethyl 2,3-dicyanopropionate (DCEP) over a period of 1hr at 25-30°C. After DCEP addition the reaction mass was stirred at 25-300C for 8hrs to obtain a product mixture. The organic layer was separated and the aqueous layer was extracted with toluene. The combined organic layer was added to 600ml of concentrated ammonia solution below 5°C over a period 2 hrs. Ammonia was bubbled to maintain the pH of the mixture above 7 and reaction was maintained at 0 to 5°C for 7hrs. Reaction was monitored on TLC and terminated when TLC showed complete consumption of the coupled mass. Excess NH3 was removed by applying vacuum till 40°C and the product obtained was filtered to yield 284g amino-pyrazole derivative (>70%) having a purity of >80%.

TECHNICAL ADVANCEMENTS
The technical advancements offered by the present disclosure include the realization of:
• Conversion of 2,6-dichloro-4-trifluoromethylaniline to 5-amino-3-cyano-1-(2,6-dichloro-4-triflouromethylphenyl)pyrazole by the disclosed process provides an economic advantage by reducing the overall cost of Fipronil synthesis.
• The overall process consumes less energy.
• The process described in this disclosure can be carried out in relatively less space owing to lesser reaction volume of the diazotization reaction mass.

Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
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.
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 invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the invention as it existed anywhere before the priority date of this application.
While considerable emphasis has been placed herein on the preferred embodiment, 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 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 preparing a substituted amino-pyrazole derivative; said process comprising of the following steps:
a. diazotizing a substituted aniline with a diazotization reagent to form a diazo compound;
b. reacting said diazo compound with an alkyl 2,3-dicyanopropionate to obtain an intermediate; and
c. adding said intermediate to an ammonia solution to obtain a reaction mass, maintaining said reaction mass at a pH ranging from 7 to 12, removing ammonia and filtering to obtain the substituted amino-pyrazole derivative.
2. The process as claimed in claim 1, wherein the substituted aniline is 2,6-dichloro-4-trifluoromethylaniline and the substituted amino-pyrazole derivative is 5-amino-3-cyano-1-(2,6-dichloro-4-triflouromethylphenyl)pyrazole.
3. The process as claimed in claim 1, wherein the diazotization reagent is selected from a group consisting of nitrosyl sulphate and sodium nitrite.
4. The process as claimed in claim 1, wherein the diazotization reagent is nitrosyl sulphate.
5. The process as claimed in claim 1, wherein the molar ratio of the substituted aniline to the diazotization reagent ranges from 1:1 to 1:1.5.
6. The process as claimed in claim 1, wherein the molar ratio of the substituted aniline to the diazotization reagent is 1:1.3.
7. The process as claimed in claim 1, wherein the step (a) is carried out in the presence of H2SO4 of concentration 60 to 90%.
8. The process as claimed in claim 1, wherein the step (a) is carried out at a temperature ranging from 30°C to 60°C.
9. The process as claimed in claim 1, wherein alkyl 2,3-dicyanopropionate is selected from a group consisting of methyl 2,3-dicyanopropionate and ethyl 2,3-dicyanopropionate.
10. The process as claimed in claim 1, wherein alkyl 2,3-dicyanopropionate is ethyl 2,3-dicyanopropionate.
11. The process as claimed in claim 1, wherein the molar ratio of the substituted aniline to alkyl 2,3-dicyanopropionate ranges from 1:0.95 to 1:1.5.
12. The process as claimed in claim 1, wherein the molar ratio of the substituted aniline to alkyl 2,3-dicyanopropionate is 1:1.05.
13. The process as claimed in claim 1, wherein the step (b) is carried out in at least one solvent selected from a group consisting of toluene and ethylene dichloride.
14. The process as claimed in claim 1, wherein the step (b) is carried out in toluene as solvent.
15. The process as claimed in claim 1, wherein the step (b) is carried out at a temperature ranging from 10°C to 50°C.
16. The process as claimed in claim 1, wherein the concentration of ammonia solution ranges from 10N to 13N.
17. The process as claimed in claim 1, wherein the step (c) is carried out at a temperature ranging from -5°C to 10°C.

Dated this 20th day of May, 2014

MOHAN DEWAN
OF R.K. DEWAN & CO.
APPLICANTS’ PATENT ATTORNEY