Indian Patents. 277245:''AN IMPROVED PROCESS FOR MANUFACTURING 5-AMINO-1-(2, 6-DICHLORO-4-TRIFLUOROMETHYLPHENYL)-3-CYANO-4-TRIFLUOROMETHYL SULPHINYL PYRAZOLE''

Title of Invention	''AN IMPROVED PROCESS FOR MANUFACTURING 5-AMINO-1-(2, 6-DICHLORO-4-TRIFLUOROMETHYLPHENYL)-3-CYANO-4-TRIFLUOROMETHYL SULPHINYL PYRAZOLE''
Abstract	The present invention relates to a process for the preparation of a compound of formula (I); CN SOCF3 [I] said process comprising oxidizing a compound of formula (II) [II] in a medium comprising at least one oxidizing agent, a solvent system and a corrosion inhibiting compound.

Full Text	FORM 2 The Patent Act 1970, (39 of 1970 The Patent rule 2003 COMPLETE SPECIFICATION (See Section 10 and Rule 13) A PROCESS FOR MANUFACTURING 5-AMINO-1-(2,6-DICHLORO-4- TRIFLUOROMETHYLPHENYL)-3-CYANO-4-TRIFLUOROMETHYL SULPHINYL PYRAZOLE GHARDA KEKI HORMUSJI an Indian National of GHARDA HOUSE, 48. HILI. ROAD, BANDRA (WEST), MUMBAI 400 050, INDIA. THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED. FIELD OF THE INVENTION The present invention relates to a process for preparing 5-amino-l-(2,6-dichloro-4- trifluoromethylphenyI)-3-cyano-4-trifluoromethyl sulphinyl pyrazole. BACKGROUND OF THE INVENTION. Fipronil [5-Amino- I -(2,6-dichloro-4-trifluoromethylphenyI)-3-cyano-4-trifluoromethyl sulphinyl pyrazole] is one of the important fluorine bearing 1-Aryl pyrazole derivatives developed in the recent two decades. It is a novel pesticide characterized by high efficiency, low toxicity and especially low residue. There are various routes to synthesize fipronil by oxidation of thiopyrazole with various other oxidizing agents in suitable solvents. The known commercial processes for manufacture of fipronil using corrosive and expensive chemical such as trifluoroacetic acid/hydrogen peroxide, m-chloroperbenzoic acid/dichloromethane/chloroform and the like have implication from commercial point of view namely,'use of expensive trifluoroacetic acid in large quantities as well as use of m- chloroperbenzoic acid which is difficult to handle at commercial scale due to it's unstability and detonating effect. Oxidation of sulfides is a very useful route for the preparation of sulfoxides. Literature is replete with the conversion of sulfides to sulfoxides and/or sulfones. However, most of the existing methods use expensive, toxic or rare oxidizing reagents, which are difficult 2 to prepare and use them at commercial scale. Many of these processes suffer from poor selectivity. A number of oxidants like sodium vanadate, sodium tungstate, peracetic acid, performic acid and pertrifluoroacetic acid have been employed in an attempt to obtain regioselective oxidation to provide 5-amino-l-(2,6,-dichloro-4-trifluoromethylphenyl)-3- cyano-4-trifluoromethyl sulphinylpyrazole. WO 01/30760 describes oxidation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)- 3-cyano-4-trifluoromethyl thio-pyrazole with trifluoroacetic acid and hydrogen peroxide in presence of boric acid. The quantity of trifluoroacetic acid used is 1610 g/mole (14.08 m/m). European Patent publication No.295117 describes the preparation of 5-amino-l-(2,6- dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulphinylpyrazole by the oxidation of 5-amino- I (2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole with 3-chloroperbenzoic acid in chloroform. The oxidation of electron deficient sulfides such as trifluoromethylsulfides, which are less readily oxidised than other sulfides, entails several difficulties. The molecule has to be stable under the desired conditions of oxidation and oxidation should proceed to the desired extent with minimum of by products such as formation of sulfonyl and amide derivatives. At the same time, level of starting material should be very low such so that product of acceptable quality can be achieved. Oxidants such as peracids, peroxides, persulfates have been widely used for effecting the oxidation. 3 Various organic solvents such as trifluroacetic acid, mixtures of trichloro/dichloroacetic acid, dichloromethane and chloroform are employed to bring about the oxidation of 5- amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio-pyrazole. Use of mineral acid as a medium is not useful due to instability of the compound towards strong mineral acids. Trifluoroacetic acid and trichloroacetic acid were found to be very efficient and regioselective oxidation medium for oxidation of 5-amino-l-(2,6-dichloro-4- trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio-pyrazole in the presence of hydrogen peroxide. However, trichloroacetic acid 'can not be used alone due to higher melting point and need to be used in presence of a melting point depressant. Trifluoroacetic acid on the other hand is very regioselective with respect to conversion and low by-products formation. However, it suffers with disadvantages such as it is expensive, water miscible, corrosive to metal as well as glass, comparatively lower boiling and it's recovery (in anhydrous form) is complex in nature. Accordingly, it is desired to develop a substitute for corrosive and expensive solvent (trifluoro acetic acid) for the synthesis of 5-amino-l-(2,6-dichloro-4- trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulphinyl pyrazole and a process employing such inexpensive, easily available but effective alternative solvent. 4 OBJECT OF THE INVENTION It is an object of the present invention to provide a process for the preparation of 5- Amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulphinyl pyrazole. It is another object of the present invention to provide a process for the preparation of 5- amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulphinyl pyrazole with reduced consumption of trifluoroacetic acid without affecting the selective degree of oxidation, yield and quality of the final product. It is yet another object of the present invention to provide a process for the preparation of 5 -amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulphinyl pyrazole which is simple, safe, convenient,. easy to operate on commercial scale and cost- effective. It is a further another object of the present invention to provide a process for the preparation of 5 -amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4- trifluoromethyl sulphinyl pyrazole which provides highly pure product with high yield. SUMMARY OF THE INVENTION In accordance with the present invention there is provided a process for the preparation of a compound of formula (I); 5 [I] said process comprising oxidizing a compound of formula (II) [II] in a medium comprising at least one oxidizing agent, a solvent system and a corrosion inhibiting compound. Typically, the oxidizing agent is a peroxide compound selected from the group consisting of hydrogen peroxide, tert butyl hydrogen peroxide, benzoyl peroxide and sodium peroxide. Preferably, the oxidizing agent is hydrogen peroxide. 6 Typically, the solvent system comprises at least one solvent selected from the group consisting of trichloroacetic acid, trifluoroacetic acid, chlorobenzene, dichloromethane and dichloroethane. In accordance with one of the preferred embodiments'of the present invention the solvent system comprises trifluoroacetic acid and chlorobenzene in a ratio of 60 : 40 % w/w to 55: 45% w/w. In accordance with another preferred embodiment, of the present invention the solvent system comprises triflhoroacetic acid and trifluoroacetic acid in a ratio of 80: 20% w/w. Typically, the proportion of hydrogen peroxide used is about 1.05 to about 1.2 moles per mole of the compound of formula II. Typically, the concentration of hydrogen peroxide is in the range of about 45 to about 70% w/w. Typically, at least one of the corrosion inhibiting compounds is boric acid. Typically, the amount of corrosion inhibiting compound employed is about 2g/m to l Og/m of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio pyrazole. Preferably, the amount of corrosion inhibiting compound employed is about 4g/m to 6g/m of 5-amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio pyrazole. Typically, the process is carried out at a temperature in tht range of about 0 to 50°C. Preferably, the process is carried out at a temperature in the range of about 10 to 30°C. DETAILED DESCRIPTION OF THE INVENTION Several process problems are encountered when trifluoro acetic acid (TFA) is used as a solvent for oxidation of 5-amino-1 -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4- trifluoromethyl thio pyrazole with 50 % aqueous hydrogen peroxide. The main problem is selection of material of construction of equipment for conducting the experiment. Due to corrosive environment under the oxidation condition, both MSGL and SS reactor can not be normally used. WO 01/30760 discloses a process for the preparation of fipronil using trifluoroacetic acid in an amount of about 14.4 m/m of thio pyrazole. It further discloses addition of corrosion inhibiting compounds such as boric acid to the reaction mixture to inhibit the corrosion and reduces the speed of corrosion to a level, which permits the use of glass reactor. However, the process disclosed in WO 01/30760 suffers with several disadvantages such as trifluoroacetic acid is a costly religent and its process economy 8 depends on its recovery and recycles. Further, trifluoroacetic acid is wet because it forms azeotrope with water, (water from aqueous hydrogen peroxide) and to get anhydrous trifluoroacetic acid from this requires azeotropic distillation in presence of concentrated H,S04. Moreover, residual TFA is converted to its alkyl ester (methyl, ethyl and others), which needs to be converted back to TFA. Thus, use of TVA as a solvent for oxidation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio pyrazole is difficult and expensive from commercial point of view. Therefore, the present invention is centered on finding a solution to this problem by selecting a solvent or a mixture of solvent which provides selective degree of oxidation as that of trifluoroacetic acid. In accordance with the present invention there is provided a process for the preparation of a compound of formula (I). [I] The process in accordance with the present invention comprising oxidizing a compound of formula (II) 9 Cl N Cl [II] in a medium comprising at least one oxidizing agent, a solvent system and a corrosion inhibiting compound to obtain a compound of formula (I). The oxidizing agent employed in the reaction is a peroxide compound selected from the group consisting of hydrogen peroxide, tert butyl hydrogen peroxide, benzoyl peroxide and sodium peroxide. In accordance with the preferred embodiment of the present invention the oxidizing agent employed is hydrogen peroxide. In accordance with the present invention the solvent system comprises at least one solvent selected from the group consisting of trichloroacetic acid, trifluoroacetic acid, chlorobenzene, dichloromethane and dichloroethane. In accordance with one of the preferred embodiments of the present invention the solvent system comprises trifluoroacetic acid and chlorobenzene in a ratio of 60 : 40 % w/w to 55: 45% w/w. 1 0 In accordance with another preferred embodiment of the present invention the solvent system comprises trichloroacetic acid and trifluoroacetic acid in a ratio of 80: 20% w/w. The quantity of peroxide used depends on required optimal conversion with minimum by product formation such as sulfone and amide derivative. In accordance with the preferred embodiment of the present invention the proportion of hydrogen peroxide used is about 1.05 to about 1.2 moles per mole of the compound of formula II. The sulfone derivative formed under this condition is less than 1.8 to 2.5 % w/w. In accordance with the present invention the concentration of hydrogen peroxide used in the reaction is in the range of about 45 to about 70% w/w. In accordance with the present invention one of the corrosion inhibiting compounds employed in the reaction is boric acid. Typically, the amount of corrosion inhibiting compound employed is about 2g/m to I Og/m of 5-amino-I -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio pyrazole. Preferably, the amount of corrosion inhibiting compound employed is about 4g/m to 6g/m of 5-amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3 -cyano-4-trifluoromethyl thio pyrazole. The reaction temperature is chosen so as to have selective kinetics of oxidation as well as the stability of the peracid under the reaction condition. Therefore, in accordance with the present invention the process is carried out at a temperature in the range of about 0 to 50°C. In accordance with the preferred embodiment of the present invention the process is carried out at a temperature in the range of about 10 to 30°C. The following examples are merely illustrative of the invention and should not be construed as limiting. Example 1 180 g of a solvent mixture (TFA: MCB =60:40 %w/w) containing trifluoroacetic acid (TPA) (108 g) and chlorobenzene (72 g) was charged in a reactor. To this 50.6 g (0.12m) of 5-amino-I-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio- p3 - and the mixture was cooled to 10- 22 °C. Them boric acid (0.60 g) was added to.above cc,oled mixture. To this 10.4 g (0.144 m) of 47 % aqueous hydrogen peroxide solution was added in lots over a period of about 1 hour. The resulting mixture was maintained at 10-12 °C for 10.5 hours. As the reaction proceeded, the solid product (fipronil) precipitated out from the reaction mass and the reaction mixture became thick stirrable slurry. The reaction was continued until the conversion was more than 93 % as measured by HPLC with 12 by destroying excess peroxide by passing sulfur dioxide and then distilling TFA/ chlorobenzene at 45 °C liquid temperature at 80 mm absolute pressure. To this mixture 150 ml of chlorobenzene and 15 ml of methanol were added and stirred at 45 °C for 2 hours. The resulting mass was neutralized with aq. NaHCO3 solution. The obtained cake was then filtered and washed with chlorobenzene. Finally, the cake was steam distilled and vacuum dried at 140 °C to get 49.3 g (89.3 % yield) crop-1 with 95.2% Fipronil content determined by HPLC external standard method. Example 2 104 g of a solvent mixture (trifluoroacetic acid: chlorobenzene = 54:46% w/w) containing trifluoroacetic acid (56g) and. chlorobenzene (48 g) was transferred in a reactor. To this boric acid (0.4 g) and 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)- 3-cyano-4-trifluoromethyl thiopyrazole (33.68 g, 0.08 m, 99.5 %) were added to obtain a mixture. The mixture was then cooled to 10-12 °C. To this cooled mixture 6.95 g (0.096 m) of 47 % hydrogen peroxide was added'in lots over a period of about 1 hour and the mixture was then stirred at 10-12 °C for 12 hours. Excess peroxide was destroyed by passing sulfurdioxide gas and trifluoroacetic acid was vacuum distilled up to 45 °C liquid temperature at 80 mm absolute pressure. The reaction mixture was worked up as above by adding chlorobenzene, methanol and neutralizing the mixture with aqueous NaHCO3 and filtration. The obtained cake was then steam distilled, filtered and vacuum dried at 140 °C to get 32.9 g (90.2 % yield) crop-I with 93.2 % Fipronil content determined by HPLC external standard method. 13 Example 3 300 g of a solvent mixture containing triflhoroacetic acid (240 g) and trifluoroacetic acid (60 g) was charged in a reactor followed by addition of boric acid (1 g) to obtain a reaction mass which was then stirred at 30 °C. To this 84.5 g (0.20 m; 99.7 %) of 5- amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole was added and the resultant mixture was cooled to .15 °C. 1.15 m/m of 50.5 % hydrogen peroxide was added in lots over 1.5 hours to above mixture and stirred at 15 °C for 16 hours to get 91 % Fipronil conversion. The reaction mixture was worked up by adding 240 ml chlorobenzene; adding water to get 50 % trichloroacetic acid and filtering the crop at 20 °C. After work up as above, 69.2 g (79.15 %) of crop-I was obtained with 96.5 % Fipronil content. by HPLC external standard. Example 4 17.3 g of methane sulfonic acid was charged in a reactor followed by addition of 9.4 g' (0.06 m) of m-chlorobenzoic acid and 25 ml dichloromethane to obtain a mixture. The mixture was then cooled to 25 °C and to this 2.6 g (0.06 m) of 78 % hydrogen peroxide was added. The mixture was stirred at 25 °C for 3 hours. 50 ml additional dichloromethane was added to the above mixture of m-chloroperbenzoic acid to get stirrable mass. 84 ml of dichloromethane was charged in another reactor and to this 21.05 g (0.05 m, 99.2 %) of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl 14 thiopyrazole was added. The resultant mixture was cooled to 13-15 °C. To this, slurry of m-chloroperbenzoic acid as prepared above was added in lots over a period of 6 hours. The mixture was stirred at 15 °C. HPLC analysis showed 27 % Fipronil conversion after 5 hours and 29.9 % conversion after 10 hours of maintenance at 15 °C . To this was added 0.5 m/m of 78 % hydrogen peroxide in lots and the reaction temperature was raised to 25 °C. HPLC analysis showed 46 % Fipronil conversion after further 12 hours of maintenance at 25 °C. Example 5 50 g of a solvent mixture containing trichloroacetic acid, dichloroacetic acid and monochloroacetic acid (gle ratio = 33: 57:10 % w/w) was charged in a reactor. To this 13 g (0.0308 m, 99.9 %) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4- trifluoromethyl thiopyrazole was added and the mixture was cooled to 8-10 °C. To this mixture 2.8 g'( 0.8 m/m ) of 81 % tert-butyl hydrogen peroxide was added in lots over a period of 2 hours. The mixture was then maintained for 15 hours at 10 °C and 8 hours at 30 °C. HPLC analysis showed only 2.9 % Fipronil. , Technical advance: The process disclosed in the present invention employs inexpensive, easily available and effective solvent as a substitute for corrosive and expensive solvent for the synthesis of f i pronil. Further, the process disclosed in the present invention particularly, employs a mixture of solvents in particular proportion, which in turn provides effective degree of oxidation and results in high yield of the fipronil. Still further, the process disclosed in the present invention is simple, safe, convenient, easy to operate on commercial scale and cost- effective. While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of'the invention 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 invention and not as a limitation. I claim: 1. A process for the preparation of a compound of formula (I); Cl CN N- CI NH2 SOCF3 [I] said process comprising oxidizing a compound of formula (11) [II] in a medium comprising at least one oxidizing agent, a solvent system and a corrosion inhibiting compound. 2. The process as claimed in claim 1, wherein the oxidizing agent is a peroxide compound selected from the group consisting of hydrogen peroxide, tert butyl hydrogen peroxide, benzoyl peroxide and sodium peroxide. 3. The process as claimed in claim 1, wherein the oxidizing agent is hydrogen peroxide. 4. The process as claimed in claim 1, wherein the solvent system comprises at least one solvent selected from the group consisting of trichloroacetic acid, trifluoroacetic acid, chlorobenzene, dichloromethane and dichloroethane. 5. The process as claimed in claim 1, wherein the solvent system comprises trifluoroacetic acid and chlorobenzene in a ratio of 60 : 40 % w/w to 55: 45% w/w. 6. The process as claimed in claim 1, wherein the solvent system comprises trichloroacetic acid and trifluoroacetic acid in a ratio of 80: 20% w/w. 7. The process as claimed in claim 3, wherein the proportion of hydrogen peroxide used is about 1.05 to about 1.2 moles per mole of the compound of formula-II. 8. The process as claimed in claim 3, wherein the concentration of hydrogen peroxide is in the range of about 45 to about 70% w/w. 9. The process as claimed in claim 1, wherein at least one of the corrosion inhibiting compounds is boric acid. 10. The process as claimed in claim 1, wherein the amount of corrosion inhibiting compound employed is about 2g/m to 1.0g/m of 5-amino-l-(2,6-dichloro-4- trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio pyrazole. 1 ] The process as claimed in claim 1, wherein the amount of corrosion inhibiting compound employed is about 4g/m to 6g/m of 5-amino-l-(2,6-dichloro-4- trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio pyrazole. 12. The process as claimed in claim 1, wherein the process is carried out at a temperature in the range of about 0 to 50°C. 13. The process as claimed in claim 1, wherein the process is carried out at a temperature in the range of about 10 to 30°C.

Full Text

FORM 2
The Patent Act 1970,

(39 of 1970

The Patent rule 2003

COMPLETE SPECIFICATION
(See Section 10 and Rule 13)

A PROCESS FOR MANUFACTURING 5-AMINO-1-(2,6-DICHLORO-4-
TRIFLUOROMETHYLPHENYL)-3-CYANO-4-TRIFLUOROMETHYL SULPHINYL PYRAZOLE

GHARDA KEKI HORMUSJI
an Indian National of
GHARDA HOUSE, 48. HILI. ROAD,
BANDRA (WEST),
MUMBAI 400 050, INDIA.

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

FIELD OF THE INVENTION

The present invention relates to a process for preparing 5-amino-l-(2,6-dichloro-4-

trifluoromethylphenyI)-3-cyano-4-trifluoromethyl sulphinyl pyrazole.

BACKGROUND OF THE INVENTION.

Fipronil [5-Amino- I -(2,6-dichloro-4-trifluoromethylphenyI)-3-cyano-4-trifluoromethyl
sulphinyl pyrazole] is one of the important fluorine bearing 1-Aryl pyrazole derivatives
developed in the recent two decades. It is a novel pesticide characterized by high
efficiency, low toxicity and especially low residue. There are various routes to synthesize
fipronil by oxidation of thiopyrazole with various other oxidizing agents in suitable
solvents.
The known commercial processes for manufacture of fipronil using corrosive and expensive chemical such as trifluoroacetic acid/hydrogen peroxide, m-chloroperbenzoic acid/dichloromethane/chloroform and the like have implication from commercial point of view namely,'use of expensive trifluoroacetic acid in large quantities as well as use of m-
chloroperbenzoic acid which is difficult to handle at commercial scale due to it's unstability and detonating effect.
Oxidation of sulfides is a very useful route for the preparation of sulfoxides. Literature is
replete with the conversion of sulfides to sulfoxides and/or sulfones. However, most of
the existing methods use expensive, toxic or rare oxidizing reagents, which are difficult

2

to prepare and use them at commercial scale. Many of these processes suffer from poor selectivity. A number of oxidants like sodium vanadate, sodium tungstate, peracetic acid, performic acid and pertrifluoroacetic acid have been employed in an attempt to obtain regioselective oxidation to provide 5-amino-l-(2,6,-dichloro-4-trifluoromethylphenyl)-3-
cyano-4-trifluoromethyl sulphinylpyrazole.
WO 01/30760 describes oxidation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-
3-cyano-4-trifluoromethyl thio-pyrazole with trifluoroacetic acid and hydrogen peroxide
in presence of boric acid. The quantity of trifluoroacetic acid used is 1610 g/mole (14.08
m/m).

European Patent publication No.295117 describes the preparation of 5-amino-l-(2,6-
dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulphinylpyrazole by the oxidation of 5-amino- I (2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole with 3-chloroperbenzoic acid in chloroform.

The oxidation of electron deficient sulfides such as trifluoromethylsulfides, which are less readily oxidised than other sulfides, entails several difficulties. The molecule has to be stable under the desired conditions of oxidation and oxidation should proceed to the desired extent with minimum of by products such as formation of sulfonyl and amide derivatives. At the same time, level of starting material should be very low such so that product of acceptable quality can be achieved. Oxidants such as peracids, peroxides, persulfates have been widely used for effecting the oxidation.

3

Various organic solvents such as trifluroacetic acid, mixtures of trichloro/dichloroacetic acid, dichloromethane and chloroform are employed to bring about the oxidation of 5-
amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio-pyrazole. Use of mineral acid as a medium is not useful due to instability of the compound towards strong mineral acids.
Trifluoroacetic acid and trichloroacetic acid were found to be very efficient and
regioselective oxidation medium for oxidation of 5-amino-l-(2,6-dichloro-4-
trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio-pyrazole in the presence of hydrogen peroxide. However, trichloroacetic acid 'can not be used alone due to higher melting point and need to be used in presence of a melting point depressant. Trifluoroacetic acid on the other hand is very regioselective with respect to conversion and low by-products formation. However, it suffers with disadvantages such as it is expensive, water miscible, corrosive to metal as well as glass, comparatively lower boiling and it's recovery (in anhydrous form) is complex in nature.

Accordingly, it is desired to develop a substitute for corrosive and expensive solvent

(trifluoro acetic acid) for the synthesis of 5-amino-l-(2,6-dichloro-4-
trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulphinyl pyrazole and a process employing such inexpensive, easily available but effective alternative solvent.

4

OBJECT OF THE INVENTION
It is an object of the present invention to provide a process for the preparation of 5-
Amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulphinyl
pyrazole.

It is another object of the present invention to provide a process for the preparation of 5-
amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulphinyl
pyrazole with reduced consumption of trifluoroacetic acid without affecting the selective degree of oxidation, yield and quality of the final product.

It is yet another object of the present invention to provide a process for the preparation of
5 -amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulphinyl
pyrazole which is simple, safe, convenient,. easy to operate on commercial scale and cost-
effective.

It is a further another object of the present invention to provide a process for the
preparation of 5 -amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-
trifluoromethyl sulphinyl pyrazole which provides highly pure product with high yield.

SUMMARY OF THE INVENTION
In accordance with the present invention there is provided a process for the preparation of a compound of formula (I);

5

[I]

said process comprising oxidizing a compound of formula (II)

[II]
in a medium comprising at least one oxidizing agent, a solvent system and a corrosion inhibiting compound.
Typically, the oxidizing agent is a peroxide compound selected from the group consisting
of hydrogen peroxide, tert butyl hydrogen peroxide, benzoyl peroxide and sodium
peroxide.

Preferably, the oxidizing agent is hydrogen peroxide.

6

Typically, the solvent system comprises at least one solvent selected from the group consisting of trichloroacetic acid, trifluoroacetic acid, chlorobenzene, dichloromethane and dichloroethane.

In accordance with one of the preferred embodiments'of the present invention the solvent system comprises trifluoroacetic acid and chlorobenzene in a ratio of 60 : 40 % w/w to 55: 45% w/w.

In accordance with another preferred embodiment, of the present invention the solvent
system comprises triflhoroacetic acid and trifluoroacetic acid in a ratio of 80: 20% w/w.
Typically, the proportion of hydrogen peroxide used is about 1.05 to about 1.2 moles per mole of the compound of formula II.

Typically, the concentration of hydrogen peroxide is in the range of about 45 to about 70% w/w.

Typically, at least one of the corrosion inhibiting compounds is boric acid.

Typically, the amount of corrosion inhibiting compound employed is about 2g/m to l Og/m of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio pyrazole.

Preferably, the amount of corrosion inhibiting compound employed is about 4g/m to 6g/m of 5-amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio pyrazole.

Typically, the process is carried out at a temperature in tht range of about 0 to 50°C.

Preferably, the process is carried out at a temperature in the range of about 10 to 30°C.

DETAILED DESCRIPTION OF THE INVENTION
Several process problems are encountered when trifluoro acetic acid (TFA) is used as a
solvent for oxidation of 5-amino-1 -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-
trifluoromethyl thio pyrazole with 50 % aqueous hydrogen peroxide. The main problem is selection of material of construction of equipment for conducting the experiment. Due to corrosive environment under the oxidation condition, both MSGL and SS reactor can not be normally used.
WO 01/30760 discloses a process for the preparation of fipronil using trifluoroacetic acid
in an amount of about 14.4 m/m of thio pyrazole. It further discloses addition of

corrosion inhibiting compounds such as boric acid to the reaction mixture to inhibit the

corrosion and reduces the speed of corrosion to a level, which permits the use of glass

reactor. However, the process disclosed in WO 01/30760 suffers with several

disadvantages such as trifluoroacetic acid is a costly religent and its process economy

8

depends on its recovery and recycles. Further, trifluoroacetic acid is wet because it forms
azeotrope with water, (water from aqueous hydrogen peroxide) and to get anhydrous
trifluoroacetic acid from this requires azeotropic distillation in presence of concentrated
H,S04. Moreover, residual TFA is converted to its alkyl ester (methyl, ethyl and others),
which needs to be converted back to TFA. Thus, use of TVA as a solvent for oxidation of

5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio pyrazole

is difficult and expensive from commercial point of view.

Therefore, the present invention is centered on finding a solution to this problem by
selecting a solvent or a mixture of solvent which provides selective degree of oxidation as that of trifluoroacetic acid.
In accordance with the present invention there is provided a process for the preparation of a compound of formula (I).

[I]
The process in accordance with the present invention comprising oxidizing a compound of formula (II)

9

Cl

N

Cl

[II]
in a medium comprising at least one oxidizing agent, a solvent system and a corrosion inhibiting compound to obtain a compound of formula (I).
The oxidizing agent employed in the reaction is a peroxide compound selected from the group consisting of hydrogen peroxide, tert butyl hydrogen peroxide, benzoyl peroxide and sodium peroxide.
In accordance with the preferred embodiment of the present invention the oxidizing agent employed is hydrogen peroxide.
In accordance with the present invention the solvent system comprises at least one solvent selected from the group consisting of trichloroacetic acid, trifluoroacetic acid, chlorobenzene, dichloromethane and dichloroethane.

In accordance with one of the preferred embodiments of the present invention the solvent
system comprises trifluoroacetic acid and chlorobenzene in a ratio of 60 : 40 % w/w to
55: 45% w/w.

1 0

In accordance with another preferred embodiment of the present invention the solvent
system comprises trichloroacetic acid and trifluoroacetic acid in a ratio of 80: 20% w/w.
The quantity of peroxide used depends on required optimal conversion with minimum by
product formation such as sulfone and amide derivative. In accordance with the preferred
embodiment of the present invention the proportion of hydrogen peroxide used is about
1.05 to about 1.2 moles per mole of the compound of formula II. The sulfone derivative

formed under this condition is less than 1.8 to 2.5 % w/w.
In accordance with the present invention the concentration of hydrogen peroxide used in the reaction is in the range of about 45 to about 70% w/w.
In accordance with the present invention one of the corrosion inhibiting compounds employed in the reaction is boric acid.
Typically, the amount of corrosion inhibiting compound employed is about 2g/m to I Og/m of 5-amino-I -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio pyrazole.

Preferably, the amount of corrosion inhibiting compound employed is about 4g/m to 6g/m of 5-amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3 -cyano-4-trifluoromethyl thio pyrazole.

The reaction temperature is chosen so as to have selective kinetics of oxidation as well as
the stability of the peracid under the reaction condition. Therefore, in accordance with the
present invention the process is carried out at a temperature in the range of about 0 to
50°C.

In accordance with the preferred embodiment of the present invention the process is carried out at a temperature in the range of about 10 to 30°C.
The following examples are merely illustrative of the invention and should not be construed as limiting.

Example 1

180 g of a solvent mixture (TFA: MCB =60:40 %w/w) containing trifluoroacetic acid
(TPA) (108 g) and chlorobenzene (72 g) was charged in a reactor. To this 50.6 g (0.12m)
of 5-amino-I-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio-
p3 - and the mixture was cooled to 10- 22 °C. Them boric acid (0.60 g)
was added to.above cc,oled mixture. To this 10.4 g (0.144 m) of 47 % aqueous hydrogen
peroxide solution was added in lots over a period of about 1 hour. The resulting mixture
was maintained at 10-12 °C for 10.5 hours. As the reaction proceeded, the solid product
(fipronil) precipitated out from the reaction mass and the reaction mixture became thick
stirrable slurry. The reaction was continued until the conversion was more than 93 % as
measured by HPLC with

12

by destroying excess peroxide by passing sulfur dioxide and then distilling TFA/ chlorobenzene at 45 °C liquid temperature at 80 mm absolute pressure. To this mixture 150 ml of chlorobenzene and 15 ml of methanol were added and stirred at 45 °C for 2 hours. The resulting mass was neutralized with aq. NaHCO3 solution. The obtained cake was then filtered and washed with chlorobenzene. Finally, the cake was steam distilled and vacuum dried at 140 °C to get 49.3 g (89.3 % yield) crop-1 with 95.2% Fipronil content determined by HPLC external standard method.

Example 2

104 g of a solvent mixture (trifluoroacetic acid: chlorobenzene = 54:46% w/w)

containing trifluoroacetic acid (56g) and. chlorobenzene (48 g) was transferred in a
reactor. To this boric acid (0.4 g) and 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-
3-cyano-4-trifluoromethyl thiopyrazole (33.68 g, 0.08 m, 99.5 %) were added to obtain a
mixture. The mixture was then cooled to 10-12 °C. To this cooled mixture 6.95 g (0.096
m) of 47 % hydrogen peroxide was added'in lots over a period of about 1 hour and the
mixture was then stirred at 10-12 °C for 12 hours. Excess peroxide was destroyed by
passing sulfurdioxide gas and trifluoroacetic acid was vacuum distilled up to 45 °C liquid
temperature at 80 mm absolute pressure. The reaction mixture was worked up as above
by adding chlorobenzene, methanol and neutralizing the mixture with aqueous NaHCO3
and filtration. The obtained cake was then steam distilled, filtered and vacuum dried at
140 °C to get 32.9 g (90.2 % yield) crop-I with 93.2 % Fipronil content determined by HPLC external standard method.

13

Example 3
300 g of a solvent mixture containing triflhoroacetic acid (240 g) and trifluoroacetic acid
(60 g) was charged in a reactor followed by addition of boric acid (1 g) to obtain a
reaction mass which was then stirred at 30 °C. To this 84.5 g (0.20 m; 99.7 %) of 5-
amino- l -(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole
was added and the resultant mixture was cooled to .15 °C. 1.15 m/m of 50.5 % hydrogen
peroxide was added in lots over 1.5 hours to above mixture and stirred at 15 °C for 16
hours to get 91 % Fipronil conversion. The reaction mixture was worked up by adding
240 ml chlorobenzene; adding water to get 50 % trichloroacetic acid and filtering the crop at 20 °C. After work up as above, 69.2 g (79.15 %) of crop-I was obtained with 96.5 % Fipronil content. by HPLC external standard.

Example 4
17.3 g of methane sulfonic acid was charged in a reactor followed by addition of 9.4 g'
(0.06 m) of m-chlorobenzoic acid and 25 ml dichloromethane to obtain a mixture. The
mixture was then cooled to 25 °C and to this 2.6 g (0.06 m) of 78 % hydrogen peroxide
was added. The mixture was stirred at 25 °C for 3 hours. 50 ml additional
dichloromethane was added to the above mixture of m-chloroperbenzoic acid to get stirrable mass.

84 ml of dichloromethane was charged in another reactor and to this 21.05 g (0.05 m,

99.2 %) of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl

14

thiopyrazole was added. The resultant mixture was cooled to 13-15 °C. To this, slurry of
m-chloroperbenzoic acid as prepared above was added in lots over a period of 6 hours.
The mixture was stirred at 15 °C. HPLC analysis showed 27 % Fipronil conversion after
5 hours and 29.9 % conversion after 10 hours of maintenance at 15 °C . To this was

added 0.5 m/m of 78 % hydrogen peroxide in lots and the reaction temperature was raised

to 25 °C. HPLC analysis showed 46 % Fipronil conversion after further 12 hours of

maintenance at 25 °C.

Example 5
50 g of a solvent mixture containing trichloroacetic acid, dichloroacetic acid and
monochloroacetic acid (gle ratio = 33: 57:10 % w/w) was charged in a reactor. To this 13
g (0.0308 m, 99.9 %) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-
trifluoromethyl thiopyrazole was added and the mixture was cooled to 8-10 °C. To this mixture 2.8 g'( 0.8 m/m ) of 81 % tert-butyl hydrogen peroxide was added in lots over a period of 2 hours. The mixture was then maintained for 15 hours at 10 °C and 8 hours at 30 °C. HPLC analysis showed only 2.9 % Fipronil. ,

Technical advance:
The process disclosed in the present invention employs inexpensive, easily available and
effective solvent as a substitute for corrosive and expensive solvent for the synthesis of
f i pronil.
Further, the process disclosed in the present invention particularly, employs a mixture of
solvents in particular proportion, which in turn provides effective degree of oxidation and

results in high yield of the fipronil. Still further, the process disclosed in the present
invention is simple, safe, convenient, easy to operate on commercial scale and cost-
effective.

While considerable emphasis has been placed herein on the specific steps of the preferred
process, it will be appreciated that many steps can be made and that many changes can be
made in the preferred steps without departing from the principles of the invention. These
and other changes in the preferred steps of'the invention 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 invention and
not as a limitation.

I claim:

1. A process for the preparation of a compound of formula (I);

Cl CN
N-

CI NH2 SOCF3

[I]

said process comprising oxidizing a compound of formula (11)

[II]
in a medium comprising at least one oxidizing agent, a solvent system and a corrosion inhibiting compound.

2. The process as claimed in claim 1, wherein the oxidizing agent is a peroxide
compound selected from the group consisting of hydrogen peroxide, tert butyl hydrogen peroxide, benzoyl peroxide and sodium peroxide.

3. The process as claimed in claim 1, wherein the oxidizing agent is hydrogen
peroxide.

4. The process as claimed in claim 1, wherein the solvent system comprises at least
one solvent selected from the group consisting of trichloroacetic acid,
trifluoroacetic acid, chlorobenzene, dichloromethane and dichloroethane.

5. The process as claimed in claim 1, wherein the solvent system comprises

trifluoroacetic acid and chlorobenzene in a ratio of 60 : 40 % w/w to 55: 45%

w/w.

6. The process as claimed in claim 1, wherein the solvent system comprises

trichloroacetic acid and trifluoroacetic acid in a ratio of 80: 20% w/w.

7. The process as claimed in claim 3, wherein the proportion of hydrogen peroxide

used is about 1.05 to about 1.2 moles per mole of the compound of formula-II.

8. The process as claimed in claim 3, wherein the concentration of hydrogen

peroxide is in the range of about 45 to about 70% w/w.

9. The process as claimed in claim 1, wherein at least one of the corrosion inhibiting

compounds is boric acid.

10. The process as claimed in claim 1, wherein the amount of corrosion inhibiting

compound employed is about 2g/m to 1.0g/m of 5-amino-l-(2,6-dichloro-4-

trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio pyrazole.

1 ] The process as claimed in claim 1, wherein the amount of corrosion inhibiting

compound employed is about 4g/m to 6g/m of 5-amino-l-(2,6-dichloro-4-

trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thio pyrazole.

12. The process as claimed in claim 1, wherein the process is carried out at a

temperature in the range of about 0 to 50°C.

13. The process as claimed in claim 1, wherein the process is carried out at a

temperature in the range of about 10 to 30°C.

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Patent Number

277245

Indian Patent Application Number

183/MUM/2010

PG Journal Number

48/2016

Publication Date

18-Nov-2016

Grant Date

16-Nov-2016

Date of Filing

25-Jan-2010

Name of Patentee

GHARDA KEKI HORMUSJI

Applicant Address

GHARDA HOUSE, 48 HILL ROAD, BANDRA(WEST), MUMBAI 400 050, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	GHARDA KEKI HORMUSJI	GHARDA HOUSE, 48 HILL ROAD, BANDRA(WEST), MUMBAI 400 050, INDIA.

PCT International Classification Number

A01N43/56

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA