Indian Patents. 271132:A PROCESS FOR THE SYNTHESIS OF FIPRONIL

Title of Invention	A PROCESS FOR THE SYNTHESIS OF FIPRONIL
Abstract	The present invention relates to a process for trifluoromethylsulfinyl pyrazole compound of formula I, from compound of formula III, wherein, R, R1 and R2 contain elements of halogen group respectively and R3 is a perhaloalkyl.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2006 COMPLETE Specification (See Section 10 and Rule 13) A PROCESS FOR THE SYNTHESIS OF FIPRONIL GUARDA KEKI HORMUSJI an Indian National, Gharda House, 48 Hill Road, Bandra (West), Mumbai 400 050, Maharashtra, India. THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED. Field of Invention This invention relates to a process for preparing trifluoromethylsulfinyl pyrazole derivatives. Particularly, the present invention envisages a process for preparing 5-Amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulfmyl pyrazole also known as Fipronil. Background and Prior Art 5-Amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulfinyl pyrazole or 5-Amino-[2,6-dichloro-4-(trif]uoromethyl)phenyl]-4-[-(1 (R,S)-trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile also known as Fipronil 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. 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 to prepare, are very expensive and cannot be used on commercial scale. Many of these processes suffer from poor selectivity. WO01/30760 describes oxidation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole with trifluoro-acetic acid and hydrogen peroxide in the presence of boric acid. The quantity of trifluoroacetic acid used is 14.5 molar equivalents. The patent also discloses the preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethyl phenyl)-3-cyano-4-trifluoromethylthio-pyrazole from 5-amino-1-(2,6- dichloro-4-trifluoromethyl phenyl)-3-cyano pyrazole-4-yl disulphide. European Patent publication No.295117 describes the preparation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulphinyl pyrazole starting from 2,6-Dichloro-4-trifluoromethylaniline to give an intermediate 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole which is oxidized with meta-chloroperbenzoic acid in chloroform to give desired product. Oxidizing agents such as perbenzoic acids do not provide effective and regioselective oxidation of electron deficient sulfides such as trifluoromethylsulphides which are less readily oxidized than other sulfides. Trifluoroacetic acid and trichloroacetic acid are found to be very efficient and regioselective oxidation medium for oxidation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole in presence of hydrogen peroxide. Trichloroacetic acid can not be used alone due to higher melting point. Trifluoroacetic acid on the other hand is very regioselective with respect to conversion and low by-products formation. However, 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. W000/35851/2000 talks about synthesis of 2,6-Dichloro-4-trifluoromethylaniline starting from 3,4,5-trichloro-benzotrifluoride in the presence of alkaline fluorides like lithium fluoride and ammonia in the presence of N-methylpyrrolidone at 250°C to give 97% conversion and 87% selectivity. The main drawback of the above process is the synthesis of 3,4,5-trichlorobenzotrifluoride in high yield and purity. Chlorination of p-chlorobenzotrifluoride gives a mixture of 3,4,5-trichlorobenzotrifluoride in 72% GLC conversions, 3,4-dichloro and tetrachlorobenzotrifluoride. The process to get pure 3,4,5-isomer from this mixture by fractionation followed by crystallization is very tedious. Moreover in-spite of using very pure intermediates, substantial amount of an undesired isomer (3-amino-4,5-dichlorobenzotrifluoride) is also obtained. Another approach to generate 3,4,5-trichlorobenzotrifluoride with high yield and purity is to perform denitrochlorination of 4-chloro-3,5-dinitrobenzotrifluoride in the presence of a catalyst as described in GB Patent 2154581A. Even though the process produces 3,4,5-trichlorobenzotrifluoide in high yield and purity, the reaction conditions are too drastic to be employed for an industrial process. The known commercial processes for the manufacture of Fipronil uses corrosive and expensive chemical such as trifluoroaceticacid, hydrogen peroxide and m-chloroperbenzoicacid Trifluoroacetic acid is expensive and generally not used in large quantities, as well as of m-chloroperbenzoic acid is difficult to handle at commercial scale due to its un-stability and detonating effect. Also the raw material used such as 2,6-Dichloro-4-trifluoromethylaniline are not easily available or made. The overall process for the Fipronil as disclosed above is found to be unsatisfactory in one respect or the other. Thus, there is felt a need for preparing Fipronil from easily available raw materials in a simple and economical manner at an industrial level, with high yields and purity. Object of the Invention The main object of the invention is to provide a convenient and economically feasible process for preparing trifluoromethylsulfinyl pyrazole compound. Another object of the present invention is to provide a process for preparing Fipronil using easily and commercially available raw materials. Yet, another object of the present invention is to provide a process for preparing Fipronil in high yield and high purity. Summary of the Invention In accordance with the present invention there is provided a process for the preparation of a trifluoromethylsulfinyl pyrazole compound of formula I, wherein, R1 and R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl said process comprising: a) halogenating an aromatic compound of formula II wherein, R is a halogen and R3 is a perhaloalkyl, to obtain a polyhalogenated perhaloalkyl benzene compound of formula III; wherein, R , R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl. b) reacting in a polar solvent, the compound of formula III with anhydrous ammonia in the presence of an alkali halide at a temperature of about 200 °C to 300 °C and a pressure of about 20 to about 50 kg/cm2 to obtain a halo-perhaloalkyl aniline compound of formula IV; wherein R2 is halogen and R3 is a perhaloalkyl. c) reacting halo-perhaloalkylaniline compound of formula IV with a halogenating agent in a solvent to obtain a product mixture containing polyhalogenated perhaloalkylaniline compound of formula V; wherein, R1 and R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl. d) isolating polyhalogenated perhaloalkylaniline compound of formula V from the product mixture; e) diazotizing the isolated polyhalogenatedperhaloalkyl aniline compound of formula V with nitrosyl sulfuric acid in the presence of an acid solvent to form a diazotized derivative of compound V; f) reacting the diazotized derivative of compound V with cyanoalkyl propionate derivative and ammonia at a temperature range of about 0 C to 25°C to obtain a reacted mixture containing pyrazole compound of formula VII; wherein, R1 and R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl. g) isolating the pyrazole compound of formula VII from the reacted mixture with a halogenated aliphatic hydrocarbon solvent followed by evaporating the solvent to yield crude pyrazole compound VII; h) sulfenylating the crude pyrazole compound of formula VII with a sulfenylating agent in an halogenated aliphatic hydrocarbon solvent to obtain a product mixture containing thio pyrazole compound of formula IX wherein, R1 and R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl. followed by isolating the thiopyrazole compound from the product mixture; and i) oxidizing the isolated thio pyrazole compound of formula IX in a reaction medium comprising a oxidizing agent , a solvent system and a corrosion inhibitor to yield a product mixture containing trifluoromethyl sulfinyl pyrazole compound of formula I. In preferred embodiment of the present invention R , R1 and R2 are chlorine, and R3 is trifluoromethyl . The polar solvent used in step (b) is selected from a group selected from a group consisting of N-methyl pyrrolidone, dimethyl sulfone, N,N'-dimethylimidazolidinone and diphenyl sulfone. Typically, the polar solvent is N-methyl pyrrolidone. Typically, the alkali halide is potassium fluoride. The reaction of compound of formula III with ammonia and alkali halide is carried at a temperature range of about 235°C to about 250°C and at a pressure of about 25 kg/cm2 to about 42 kg/cm2. The halogenating agent used to halogenate compound IV is at least one selected from a group consisting of chlorine, sulfuryl chloride, thionyl chloride and phosphorus pentachloride. Typically, the halogenating agent is sulfuryl chloride. The halogenation is carried out in a solvent, particularly a chlorinated solvent selected from a group consisting of chloroform, dichloroethane, dichloromethane, chlorobenzene and o-dichlorobenzene. Typically, the polyhalogenated perhaloalkylaniline compound of formula V is isolated from the product mixture by distillation. In preferred embodiment of the present invention, the solvent system in oxidation step (i) is a mixture of at least two solvents selected from a group of halogenated solvents consisting of trifluoroaceticacid, trichloroaceticacid, dichloroaceticacid, chlorobenzene, dichloromethane and dichloroethane. In accordance with one aspect of the present invention, the solvent system in step (i) is a mixture of trifluoroacetic acid and chlorobenzene in a ratio of 60:40% w/w to 55:45% w/w. In accordance with yet another aspect of the present invention the solvent system in oxidation step (i) is a mixture of trifluoroacetic acid and trichloroacetic acid in a ratio of 20: 80% w/vv. Typically, trifluoroacetic acid is used in the amount of 7 to 13.5 molar equivalents. In accordance with another aspect of the present invention the solvent system in oxidation step (i) is a mixture of trichloroacetic acid and chlorobenzene in a ratio of 80: 20% w/w. In accordance with yet another aspect of the present invention the solvent system in oxidation step (i) is a mixture of trichloroacetic acid, dichloroacetic acid and chlorobenzene. The chlorobenzene content in the mixture ranges from 20% to 30%w/w. Typically, trichloroaceticacid is used in the amount of 5 to 14 molar equivalents. The oxidizing agent is a peroxide compound selected from the group consisting of hydrogen peroxide, tert-butyl hydrogen peroxide, benzoyl peroxide and sodium peroxide. Typically, the oxidizing agent is hydrogen peroxide. Typically, the amount of hydrogen peroxide used is about 0.8 moles to about 1.2 moles per mole of the compound of formula IX. The corrosion inhibitor used during oxidation step (i) is boric acid. The sulfenylating agent used in step (h) is trifluoromethyl sulfenyl chloride of formula VIII. In preferred embodiment of the present invention, trifluoromethyl sulfmyl pyrazole compound I is further purified by at least one of the processes of crystallization and leaching. The crystallization is carried out using at least one solvent selected from a group consisting of toluene, chlorobenzene and ethyl acetate. In preferred embodiment of the present invention crystallized trifluoromethyl sulfinyl pyrazole compound I is further purified by leaching . Typically, the leaching trifluoromethyl sulfinyl pyrazole compound I is carried out using at least one solvent selected from a group consisting of toluene, chlorobenzene and ethyl acetate . In preferred embodiment of the present invention, the solvent mixture used for leaching is chlorobenzene and ethyl acetate. The chlorobenzene content in the mixture ranges from 5% to 100% v/v. Typically, the chlorobenzene is in the ratio 2-10 parts per part of trifluoromethylsulfinyl pyrazole compound I. Typically, the compound of formula II is 4-chlorobenzotriflouride. The compound of formula III is 3,4-dichlorobenzotriflouride. The compound of formula IV is 2-chloro-4-trifluormethylaniline. The compound of formula V is 2,6-dichloro-4-trifluormethylaniline . The cyanoalkyl propionate derivative is ethyl-2,3-dicyanopropionate of formula VI. The compound of formula VII is 5-amino-3-cyano-l-(2,6-dichloro-4-triflouro methyl phenyl)-pyrazole. The compound of formula IX is 5-amino-[2,6-dichloro-4-(trifluoromethyl) phenyl]-4-[trifluoromethylsulfenyl]-lH-pyrazole-3-carbonitrile. In preferred embodiment of the present invention the trifluoromethyl sulfinyl pyrazole compound of formula I is 5-amino-[2,6-dichloro-4-(trifluoromethyl) phenyl]-4-[-(l(R,S)-trifluoro methyl) sulfinyl]-lH-pyrazole-3-carbonitrile. Typically, the purity of 5-amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[- (l(R,S)-trifluoromethyl)sulfmyl]-lH-pyrazole-3-carbonitrile is greater than 98%. Detailed Description of the Invention The process for trifluoromethyl sulfinyl pyrazole compound of formula I is illustrated with reaction sequence as depicted below in scheme 1. Scheme I In accordance with the present invention polyhalogenated perhaloalkyl benzene compound of formula III is manufactured in high yields and purity by chlorination of aromatic compound of formula II . In preferred embodiment of the present invention compound II is p-chlorobenzotrifluoride. Ammonolysis of polyhalogenated perhaloalkyl benzene compound of formula III to obtain halo-perhaloalkylaniline compound of formula IV is easier and facile as compared to that of p-chlorobenzotrifluoride (compound II) and much higher conversions as compared to that of p-chlorobenzotrifluoride. Polyhalogenated perhaloalkyl benzene compound of formula III is ammonolyzed with anhydrous ammonia in the presence of a solvent. Ammonolysis is conducted in the presence of alkali halides under pressure at 20 to 50 kg/cm2 and in a temperature range of about 200°C to about 300°C. Catalytic amounts of copper compound may be used during ammonolysis. The alkali halide is preferably potassium fluoride. Anhydrous ammonia is used in excess of 2-6 m/m to start with. As the reaction proceeds, more ammonia is fed to maintain the reactor pressure and to minimize side reactions, which predominate at higher temperature due to lowering of ammonia concentrations. In a preferred embodiment of the present invention, the solvent employed in the present process can be any solvent or a mixture of solvent, which do not decompose under the reaction conditions and is inert with respect to the reactants. Preferably the solvent used is a polar solvent. The polar solvent is selected from a group consisting of N-methyl pyrrolidine, N,N'-dimethylimidazolidinone, diphenyl sulfone and dimethylsulfone. N-methylpyrrolidone is the solvent of choice as it does not interact with the reactants and at the same time it solubilises potassium fluoride. Halo-perhaloalkylaniniline compound is further halogenated to polyhalogenated perhaloalkyl aniline compound of formula V, halogenation is is carried out using atleast one of the halogenating agents selected from the group consisting of chlorine, thionyl chloride, sulfuryl chloride and PC15 at temperatures ranging between 0°C to 100°C, preferably 0°C to 70°C. The preferred halogenating agent is sulfuryl chloride. Among various halogens, the preferred halogen is chlorine unless a specific halogen is desired. The amount of halogenating agent used is limited to 10 to 50% excess, relative to the stoichiometric amount, preferably about 10-20% excess of the stoichiometric amount. Preferably, halogenation is done in chlorinated hydrocarbon solvents. The preferred solvents are chloroform, dichloroethane, dichloromethane, chlorobenzene and o-dichlorobenzene. In preferred embodiment of the present invention, the compound of formula V is 2,6-dichloro-4-trifluoromethylaniline. It is further purified by fractional distillation of the product post halogenation. Distilled product can be crystallized from a suitable solvent to achieve the desired quality. 2,6-Dichloro-4-trifluoromethylaniline is diazotized with nitrosyl sulfuric acid in acid solvent and then treated with ethyl cyanopropionate compound and ammonia at a temperature ranging from 0 to 25 °C to give pyrazole derivative of formula VII, the pyrazole compound is further extracted from the reaction mixture by using halogenated aliphatic hydrocarbon. The solvent is then removed to isolate crude pyrazole. In a preferred embodiment of the present invention, cyanoalkyl propionate derivative is ethyl-2,3-dicyanopropionate. Crude pyrazole of formula VII is sulfenylated with a sulfenylating agent to give thiopyrazole compound of formula IX, the reaction is carried out in halogenated aliphatic hydrocarbon solvent. Thiopyrazole compound is further isolated by the distillation of the solvent. In preferred embodiment of the present invention the sulfenylating agent is trifluoromethyl sulfenyl chloride. Thiopyrazole compound of formula IX is then oxidized to trifloromethyl sulfmylpyrazole compound of formula I, the oxidation is carried out in medium containing a solvent and a oxidizing agent. The oxidizing agent is selected from a group consisting of hydrogen peroxide, tert-butyl hydrogen peroxide, benzoyl peroxide and sodium peroxide. Most preferred oxidizing agent is hydrogen peroxide. The oxidation is carried out in the presence of corrosion inhibitor such as boric acid. The amount of hydrogen peroxide used is about 1.05 moles to about 1.2 moles per mole of the compound of formula IX. The solvent used for oxidation is a mixture of at least two solvents selected from a group consisting of trifluoroacetic, trichloroacetic acid, chlorobenzene, dichloromethane and dichloroethane. In accordance with another aspect of the present invention the solvent system in oxidation step (i) is a mixture of trichloroacetic acid and chlorobenzene in a ratio of 80: 20% w/w. In accordance with another aspect of the present invention the solvent system in step (i) is a mixture of trichloroaceticacid, dichloroaceticacid and chlorobenzene in a ratio of 70:30 - 80:20% w/w. Typically, trichloroacetic acid is used in the amount of 5 to 14 molar equivalents. In another aspect of the present invention oxidation is carried out using a mixture of trifluoroacetic acid and trichloroacetic acid in a ratio of 20: 80% w/w. In one aspect of the present invention oxidation is carried out using a mixture of trifluoroacetic acid and chlorobenzene in a ratio of 60:40% w/w to 55:45% w/w. Total amount of the trifluoroacetic acid used is 7 to 13.5 molar equivalents. The quantity of peroxide used depends on required optimal conversion with minimum by-product formation such as sulfone derivative. In preferred embodiment of the present invention compound of formula IX is 5-Amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[-(-trifluoromethyl) sulfenyl]-lH-pyrazo.le-3-carbonitrile. In preferred embodiment of the present invention compound of formula I is (5-Amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[-(l(R,S)- trifluoromethyl)sulfmyl]-lH-pyrazole-3-carbonitrile). Crude Fipronil (5-Amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[-(l(R,S)-trifluoromethyl)sulfinyl]-lH-pyrazole-3-carbonitrile), formula I thus formed is isolated by removing the solvent. Crude Fipronil is further purified by crystallization using at least one solvent selected from a group consisting of esters of aliphatic acids and halogenated aromatic hydrocarbons, mainly ethylacetate and chlorobenzene. The solvent mixture is used depending upon the associated impurities present in fipronil. Crystallized fipronil is further subjected to leaching using a solvent and/or a mixture of solvents selected from chlorobenzene and ethyl acetate.. The fipronil thus obtained after crystallization and leaching has the purity of above 98%. The invention is further illustrated with respect to the following examples which do not limit the scope of the invention in any way. In the examples m/m means one gram mole of product obtained from one gram mole of substrate input. Examples Example- 1 1050 ml of N-methylpyrrolidone was charged in an autoclave along with 102 g (1 m/m) anhydrous activated potassium fluoride, 377 g (1.75 mole,) 3,4-dichlorobenzotrifluoride was added and a pressure pot was fitted to the autoclave. 158 g (5.3 m/m) ammonia gas was passed in the reactor from the pressure pot at ambient temperature. The content of the reactor was heated to 245-250°C over a period of 2 hours to get reactor pressure of 30-32 kg/cm2. Excess NH3 was fed from the pressure pot to maintain the reactor pressure at 38-40 kg/cm2 at 245-2500C liquid temperature. Reaction mixture was maintained at 245-250°C and at 38-40 kg/cm2 pressure for further 8 hours. Reaction mixture was cooled to ambient temperature, NH3 was vented and recovered. Reaction mixture on treatment and fractionation gave 77% yield of 2-chloro-4-trifluoromethylaniline and 13% yield of 2-chloro-5-trifluoro methyl aniline based on consumed 3,4-dichlorobenzotrifluoride. Example- 2 815 ml on N-methylpyrrolidone was charged in an autoclave along with 291 g 3,4-dichlorobenzotrifluoride (1.35moles) and ll8g (1.5 m/m) of calcined potassium fluoride and a pressure pot was fitted to the autoclave. 213 g (9.2 m/m) of ammonia gas was fed into the pressure pot. 158 g (6.88 m/m) of ammonia gas was passed into the reactor from the pressure pot at ambient temperature initially and then the mixture in the autoclave was gradually heated to 245-250°C liquid temperature and further maintained at temperature .245-250°C and pressure 38-40 kg/cm2 for 6 hours by feeding ammonia gas to maintain the desired reactor pressure. After fractionation the yield of 2-chloro-4-trifluoromethylaniline was 75.2% based on 3,4-dichlorobenzotrifluoride consumed. Example -3 75.4 g (0.35 moles) of 3,4-dichlorobenzotrifluoride was added to 210 ml of N-methylpyrrolidone along with 30.45 g (0.525 m) of calcined potassium fluoride & 1.73 g cuprous chloride (0.0174m) in an autoclave. Ammonia (lmole) gas was passed & the resultant reaction mixture was heated to 235°C to get a pressure of 19 kg/cm . Ammonia gas was further fed to maintain the pressure of the resultant mixture at 25-26 kg/cm for 6 hrs at 235°C reaction temperature. After fractionation the yield of 2-chloro-4-trifluoromethyl aniline was 64% based on 3,4-dichlorobenzotrifluoride consumed. Example -4 75.4 g (0.35 moles) of 3,4-dichlorobenzotrifluoride was added to 210 g of dimethylsulfone & 30.45 g (0.525 m) of calcined potassium fluoride in an autoclave. The ammonia gas (6-7 g (1-1.2 m/m)) was passed at 30°C. The resultant reaction mixture was heated to 235°C.The pressure was maintained at 25-26 kg/cm by feeding ammonia gas at regular interval of time. The reaction mixture was maintained for 6 hrs at the above temperature and pressure, was then cooled to 50°C & worked by filtration of the salt after venting and recovering ammonia followed by fractionating the mixture under reduced pressure. The yield of 2-chloro-4-trifluoromethylaniline was 84% based on 3,4-dichlorobenzotrifluoride consumed. Example -5 75.4 g (0.35 m) of 3,4-dichlorobenzotrifluoride was added to 210 ml of N,N'-dimethylimidazolidinone along with 30.45 g (0.525 m) of calcined potassium fluoride in an autoclave Ammonia gas (1 m/m) was fed and the resultant reaction mixture was heated to 235°C to get a pressure of 19 kg/cm2. Ammonia gas was further fed to maintain the pressure of the resultant mixture at 25-26 kg/cm2 for further 6 hrs at 235°C After fractionation the yield of 2-chloro-4-trifluoromethyl aniline was 71.8% based on 3,4-dichlorobenzotrifluoride consumed. Example- 6 A mixture (1.0 mole isomer mixture) (301 g) of 2-chloro-4-trifluoromethylaniline (0.88m), 2-chloro-5-trifluoromethylaniline (0.117m) and N-methyl pyrrolidone (NMP) (1.06 m/m) was mixed with 500 ml chlorobenzene. 148.4 g (1.1 m/m) of sulfuryl chloride was added to the mixture at 55-60°C over a period of 4 hours and the reaction mixture was maintained at 55-60°C for 4 hours. Reaction medium on treatment and fractionation gave 0.84 m of 2,6-dichloro-4-trifluoromethylaniline, 95% yield on 2-chloro-4-trifluoromethylaniline. Example- 7 A mixture (276 g) of 2-chloro-4-trifluoromethylaniline (0.854 m), 2-chloro-5-trifluoromethylaniline (0.147 m) and NMP (0.73 m/m) was mixed with 500 ml chlorobenzene. 135 g (1 m) sulfuryl chloride was added to the mixture at 55-60°C liquid temperature over a period of 4 hours and the reaction temperature was maintained for further 2 hours. Additional 20.2 g (0.15 m/m) of sulfuryl chloride was added for completion of reaction. Reaction medium on treatment and fractionation gave 0.809 m of 2,6-dichloro-4-trifluoromethylaniline, 94% yield on 2-chloro-4-trifluoromethylaniline. Example-8 A mixture (740 g) (2.68m) containing 2-chloro-4-trifluoromethyaniline (2.346m), 2-chloro-5-trifmoromethylaniline (0.334m) and NMP (0.686 m/m) was charged with 400 ml dichloroethane in to the reactor. It was then reacted with 430 g (3.18m) of sulfuryl chloride at 55-60 °C over a period of 4 hrs & further maintained at 65-70°C for 2 hrs. The reaction mixture was worked up by adding water & treating with 5N NaOH, the organic layer was fractionated under reduced pressure over a 5 feet column to get 504.9 g of distilled 2,6-dichloro-4-trifluoromethylaniline. The yield of 2,6-dichloro-4-trifluoromethyl aniline was 93.5% on 2-chloro-4-trifluoromethylaniline. Example-9 A mixture (0.99 m) (270g) containing 2-chloro-4-trifluoromethyl aniline (0.82 m), 2-chloro-5-trifluoromethylaniline (0.174 m) and NMP (0.676 m/m) was mixed with 210 ml chlorobenzene. It was chlorinated by passing 1.22m chlorine gas at 50-55°C over a period of 8 hrs. The reaction mixture was worked up by adding water, treating the organic layer with 5N NaOH and the organic layer was fractionated under reduced pressure over 3 feet column to get 92.5 g distilled 2,6-dichloro-4-trifluoromethylaniline. Yield was 49 % on 2-chloro-4-trifluoromethylaniline. Example 10 Sodium 38.6 g (1.68 m) was dissolved in ethanol 500 ml. The obtained sodium ethoxide solution was added to 201 g (1.76 m) of ethyl cyanoacetate over 0.5 hour to get a slurry of sodium salt of ethyl cyanoacetate. The above slurry was added to 107 g (1.77 m) of glycolonitrile in 330 ml ethanol at 5-10°C over 3 hours. The addition of slurry of sodium salt of ethyl cyanoacetate to glycolonitrile resulted in clear solution with the liberation of heat. The solution was stirred at 5-10°C for additional 1 hour and then raised the liquid temperature to 30°C-and equilibrated for 4 hours. The mixture was then cooled to 5-10°C and neutralized to pH = 4.45. The reaction mass was further equilibrated for 1 hour. The mixture was filtered at 10°C and washed the cake with ethanol. The Filtrate and wash were combined and ethanol was distilled under vacuum, the crude 2,3-dicyano-ethyl propionate thus obtained was dissolved in dichloromethane and the solution was washed with cold water followed by 10% soda ash solution. The organic layer containing 2,3-dicyanoethyl propionate was dried over magnesium sulphate. The oily layer obtained after removal of dichloromethane was distilled under reduced pressure over a column to give ethyI-2,3-dicyanopropionate in 79.6% yield. Example 11 Preparation of 5-aminopyrazole (VII): To 2,6-dichloro-4-trifluoromethyl aniline 230 g and acetic acid 150 ml was added nitrosyl sulphuric acid (prepared from 286 g sulphuric acid 98%, water 150 ml, 98% nitric acid 65g and sulphur dioxide 64 g) over one hour at 30°C and maintain at 30°C for one more hour. Heat the mass to 50-55°C over 1/2 hour and the absence of 2,6-dichloro-4-trifluoromethyl aniline was monitored. Cool the mass to 30°C, and the excess nitrosyl sulphuric acid was destroyed. The above diazotized mass was added to a mixture of 250 ml of acetic acid, 162 g ethyl-2,3-dicyanoproprionate and 425 ml water over 4-5 hours maintaining temperature 0-5°C. Further maintain at 0°C / 2 hours, 5°C / 1 hour, 10°C / lhour, 15°C / 1 hour. Add 800 ml water at 15°C over V2 hour, extract the solution with 3x250 ml methylene dichloride. Separate layers. Wash dichloromethane layer with 250 ml water, cool the dichloromethane layer to 0°C and wash with 250 ml 8N aq. NH3 under stirring for one hour. Separate layers, take dichloromethane layer, pass NH3 gas at 0-5°C till free NH3 is observed on top of the condenser and maintain the reaction mass for 3-4 hours at 0-5°C. Then add 250 ml water, stir for 1/2 hour, separate layers, extract aq. layer with 2x100 ml dichloromethane, dry dichloromethane layer with MgS04, concentrate dichloromethane layer to dryness, the yield of 5-amino pyrazole is 288 g, and the purity is 95-98%. Example 12 To a glass reactor having a central vertical stirrer, a vertical condenser & a dip tube for passing C12, was charged 730ml of 3N HC1. To this Carbon disulfide 83.4gm was added followed by 388gm C12 gas bubbled over l0hrs at 24- 25°C. Reaction was monitored by GLC & terminated when CS2 was 198gm of the product, trichlorornethylsulfenylchloride, with 93% purity was isolated by layer separation. It was purified by fractionation to give 194gm product, with 95% purity. Trichloromethylsulfenylchloride (194 gm) was added in to a mixture of 500gm water & 100ml methylene dichloride, along with 83gm Sulfur dioxide gas at 10°C, over a period of 4 hrs. Reaction was terminated, when trichloromethyi sulfenyl chloride was Thiophosgene with 45% purity was isolated by layer separation, 228 gms of thiophosgene was obtained, which was added in to 175gm activated KF, 110gm ortho-chlorobenzyl chloride, 340gm spherogel (with 2mm diameter), at 60°C, over a period of 3hrs & further maintained at 60°C for 2hrs. Conversion was 98% and 138gms O-chlorobenzyl trifluoromethylsulfide was isolated by filtration, followed by distillation. O- chlorobenzyltrifluoromethylsulfide was added to 500ml methylene chloride, cooled to 10°C & 41gm Cl2 was bubbled into it, the reaction was maintained for 2 hrs & then heated slowly to 40-45 °C, generated trifluoromethylsulfenyl chloride was passed in 5-amino-3-cyano-l-(2,6-dichloro-4-trifluorornethyl phenyl)-pyrazole, the reaction was carried out in halogenated aliphatic hydrocarbon solvent to get 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole. Yield of thiopyrazole was 90%. Example 13 A solvent mixture (180 g) (trifluoroacetic acid:ichlorobenzene, 60:40%w/w) containing trifluoroacetic acid (TFA) (108 g) and chlorobenzene (72 g) was charged in a reactor. To this 50.6 g (0.12m) of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole was added and the mixture was cooled to 10-12°C. Then boric acid (0.60 g) was added to above cooled 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 % with Example 14 A solvent mixture (104 g) (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. The reaction 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 and trifluoroacetic acid was vacuum distilled. The reaction mixture was worked up as above by adding chlorobenzene, methanol and neutralizing the mixture with aqueous NaHC03 and filtration to yield 32.9 g (88% yield) crude Fipronil of purity 93.2 %. Example 15 A solvent mixture (300 g) containing trichloroacetic acid (240 g) and trifluoroacetic acid (60 g) was charged in a reactor followed by addition of boric acid (1 g) and the reaction mass was stirred at 30°C. To this reaction mass, 84.5g (0.20m) of 5-amino-l-(2,6-dichloro-4-trifluoromethyl phenyl)-3-cyano-4-trifluoromethyl thiopyrazole was added and the resultant mixture was cooled to 15°C. 15.48 g (0.23 m) of 50.5 % aqueous hydrogen peroxide was added in lots over 1.5 hours to the above mixture and was further stirred at 15 °C for 16 hours to get 91 % Fipronil .The reaction mixture was worked up by adding 240 ml chlorobenzene and water. After work up as above, 69.2 g (76 %) of crude Fipronil of purity 96.5 % was obtained. Example 16 In to a mixture of 1200 gms of Trichloroacetic acid, 300 gms of chlorobenzene, 2 gms boric acid, added 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole 421 gms and cooled the content to 15- 20°C. 68 g (1.0 m) of 50 % aq. H202 was added and mass was stirred for 20 hrs. After work up as above, 418g (90 %) of crude Fipronil of purity 94 % was obtained .The filtered Fipronil was then purified using chlorobenzene (4 ml/g) followed by mixture (1 ml/g, 80:20 v/v) of Ethyl acetate and chlorobenzene to get 371 gms (85%) of Fipronil of greater than 97% purity. Example 17 A mixture of 700 gms of dichloroacetic acid and trichloroacetic acid was taken along with 300 gms of chlorobenzene, 2 gms boric acid and 280 gms of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole, the content were cooled to 15 - 20°C. 44.2 g (0.65 m) of 50 % aq. H202 was added and mass was stirred for 20 hrs. The mass was then processed and Fipronil was isolated by filtration. After work up as above, 269g (87 %) of crude Fipronil of purity 94 % was obtained. The filtered Fipronil was then purified using chlorobenzene (5 ml/g) followed by mixture (1 ml/g, 80:20 v/v) of Ethyl acetate and chlorobenzene to get 232 gms (80%) of Fipronil of greater than 97 % purity. Example 18 : Purification of fipronil The above fipronil of purity 97% was treated with a mixture (1 ml/mg) of ethylacetate & chlorobenzene (80:20 v/v). This reaction mixture was heated to 85-90°C & maintained for lhr. It was further cooled up to 30°C in stages & filtered. Fipronil thus obtained had a purity of 98%. This cycle was repeated to obtain fipronil of above 98% purity. The useful constituents from various streams of crystallization, leaching as above were reused and recycled, fipronil was isolated in 80-85% yield with purity of above 98%. The numerical values of various parameters given in the specification are but approximations and slightly higher or slightly lower values of these parameters fall within the ambit and the scope of the invention. While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be highly 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 disclosures 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 trifluoromethylsulfinylpyrazole compound of formula I, said process comprising: a) halogenating a aromatic compound of formula II wherein, R is a halogen and R3 is a perhaloalkyl, to obtain a polyhalogenated perhaloalkyl benzene compound of formula III; wherein, R ,R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl, b) reacting in a polar solvent, the compound of formula III with anhydrous ammonia in the presence of an alkali halide at a temperature of about 200 °C to 300 °C and a pressure of about 20 to about 50 kg/cm2 to obtain a halo- perhaloalkyl aniline compound of formula IV; wherein R2 is halogen and R3 is a perhaloalkyl, c) reacting halo-perhaloalkylaniline compound of formula IV with a halogenating agent in a solvent to obtain a product mixture containing polyhalogenated perhaloalkylaniline compound of formula V; wherein, R1and R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl, d) isolating polyhalogenated perhaloalkylaniline compound of formula V from the product mixture; e) diazotizing the isolated polyhalogenated aniline compound of formula V with nitrosyl sulfuric acid in the presence of an acid solvent to form a diazotized derivative of compound V; f) reacting the diazotized derivative of compound V with cyanoalkyl propionate derivative and ammonia at a temperature range of about 0°C to 25 °C to obtain a reacted mixture containing pyrazole compound of formula VII; wherein, R1 and R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl, g) isolating the pyrazole compound of formula VII from the reacted mixture with a halogenated aliphatic hydrocarbon solvent followed by evaporating the solvent to yield crude pyrazole compound VII; h) sulfenylating the crude pyrazole compound VII with a sulfenylating agent in a halogenated aliphatic hydrocarbon solvent to obtain a product mixture containing thio pyrazole compound of formula IX wherein, R1 and R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl, followed by isolating the thiopyrazole compound form the product mixture; and i) oxidizing the isolated thio pyrazole compound of formula IX in a reaction medium comprising a oxidizing agent , a solvent system and a corrosion inhibitor to yield a product mixture containing trifluoromethyl sulfinyl pyrazole compound of formula I. 2. The process as claimed in claim 1, wherein R, R1 and R2 are chlorine and R3 is trifluoromethyl. 3. The process as claimed in claim 1, wherein the polar solvent is selected from a group selected from a group consisting of N-methyl pyrrolidone, dimethyl sulfone,N,N'-dimethylimidazolidinone and diphenyl sulfone. 4. The process as claimed in any one of the preceding claims wherein the solvent is N-methyl pyrrolidone. 5. The process as claimed in claim 1, wherein the alkali halide is potassium fluoride. 6. The process as claimed in claim 1, wherein the reaction in step (b) is carried at a temperature range of about 235° C to about 250° C. 7. The process as claimed in claim 1, wherein the reaction in step (b) is carried at a pressure of about 25 kg/cm to about 42kg/cm. 8. The process as claimed in claim 1, wherein the halogenating agent used in step (c) is atleast one selected from a group consisting of chlorine, sulfuryl chloride, thionyl chloride and phosphorus pentachloride. 9. The process as claimed in claim 1, wherein the halogenating agent is sulfuryl chloride. 10. The process as claimed in claim 1, wherein the solvent in step (c ) is a chlorinated solvent selected from a group consisting of, chloroform, dichloroethane, dichloromethane, chlorobenzene and o-dichlorobenzene. 11. The process as claimed in claim 1, wherein the polyhalogenated perhaloalkylaniline compound of formula V is isolated from the product mixture by fractional distillation . 12. The process as claimed in claim 1, wherein the solvent system in step (i) comprises at least two solvents selected from a group of halogenated solvents consisting of trifluoroaceticacid, trichloroaceticacid, dichloroaceticacid chlorobenzene, dichloromethane and dichloroethane. 13. The process as claimed in claim 1, wherein the solvent system in step (i) is a mixture of trifluoroacetic acid and chlorobenzene in a ratio of 60:40% w/w to 55:45% w/w. 14. The process as claimed in claim 1, wherein the solvent system in step (i) is a mixture of trifluoroacetic acid and trichloroacetic acid in a ratio of 20: 80% w/w. 15. The process as claimed in any one of the preceding claims, wherein the amount of the trifluoroacetic acid is 7 to 13.5 molar equivalents. 16. The process as claimed in claim 1, wherein the solvent system in step (i) is a mixture of trichloroaceticacid , dichloroaceticacid and chlorobenzene . 17. The process as claimed in claim 16, wherein the chlorobenzene content in the mixture is about 20% to 30%w/w. 18. The process as claimed in claim 1, wherein the solvent system in step (i) is a mixture of trichloroacetic acid and chlorobenzene in a ratio of 80:20 w/w. 19. The process as claimed in any one of the preceding claims, wherein the amount of the trichloroacetic acid is 5 to 14 molar equivalents. 20. 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. 21. The process as claimed in any one of the preceding claims, wherein the oxidizing agent is hydrogen peroxide. 22. The process as claimed in any one of the preceding claims, wherein the amount of hydrogen peroxide used is about 0.8 moles to about 1.2 moles per mole of the compound of formula IX. 23. The process as claimed in claim 1, wherein the corrosion inhibitor is boric acid. 24. The process as claimed in claim 1, wherein the oxidation is carried out at a temperature 10 °C to 30 °C. 25. The process as claimed in claim 1, wherein the sulfenylating agent is trifluoromethyl sulfenyl chloride. 26. The process as claimed as claimed in claim 1, wherein the compound of formula II is 4-chlorobenzotriflouride. 27. The process as claimed as claimed in claim 1, wherein the compound of formula III is 3,4-dichlorobenzotriflouride. 28. The process as claimed as claimed in claim 1, wherein the compound of formula IV is 2-chloro-4-trifluormethylaniline. 29. The process as claimed as claimed in claim 1, wherein the compound of formula V is 2,6-dichloro-4-trifluormethylaniline . 30. The process as claimed as claimed in claim 1, wherein the cyanoalkyl propionate derivative is ethyl-2,3-dicyanopropionate. 31. The process as claimed as claimed in claim 1, wherein the compound of formula VII is 5-amino-3-cyano-l-(2,6-dichloro-4-triflouromethyl phenyl)- pyrazole. 32. The process as claimed as claimed in claim 1, wherein the compound of formula IX is 5-amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[trifluoromethyl sulfenyl]-lH-pyrazole-3-carbonitrile. 33. The process as claimed in claim 1 further comprises the step of purifying trifluoromethyl sulfinyl pyrazole compound I by at least one process selected from the process consisting of crystallization and leaching. 34. The process as claimed in claim 33, wherein the crystallization of trifluoromethyl sulfinyl pyrazole compound I is carried out using at least one solvent selected from a group consisting of toluene, chlorobenzene and ethyl acetate. 35. The process as claimed in any one of the preceding claim further comprises purification of crystallized trifluoromethyl sulfinylpyrazole compound I by leaching. 36. The process as claimed in any one of the preceding claim, wherein the leaching of trifluoromethyl sulfinyl pyrazole compound I is carried out using at least one solvent selected from a group consisting of toluene, chlorobenzene and ethyl acetate. 37. The process as -claimed in any one of the preceding claim, wherein the solvent for leaching trifluoromethylsulfinylpyrazole compound I is a mixture of chlorobenzene and ethyl acetate. 38. The process as claimed in claim 37, wherein the chlorobenzene content in the mixture ranges from 5% to 100% v/v. 39. The process as claimed in claim 36, wherein the chlorobenzene is in the ratio of 2-10 parts per part of trifluoromethylsulfinyl pyrazole compound I. 40. The process as claimed in claim 36, wherein the chlorobenzene is in the ratio of 3-4 parts per part of trifluoromethyl sulfinyl pyrazole compound I. 41. A compound 5-amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[- (l(R,S)-trifluoro methyl) sulfinyl]-lH-pyrazole-3-carbonitrile of formula I made in accordance with the process as claimed in any one of the preceding claims. 42. The process as claimed in any one of the preceding claim, wherein the purity of 5-amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[-(l(R,S)- trifluoro methyl) sulfinyl]-lH-pyrazole-3-carbonitrile is greater than 98%.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2006
COMPLETE
Specification
(See Section 10 and Rule 13)
A PROCESS FOR THE SYNTHESIS OF FIPRONIL
GUARDA KEKI HORMUSJI
an Indian National,
Gharda House, 48 Hill Road,
Bandra (West),
Mumbai 400 050,
Maharashtra, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

Field of Invention
This invention relates to a process for preparing trifluoromethylsulfinyl pyrazole derivatives.
Particularly, the present invention envisages a process for preparing 5-Amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulfmyl pyrazole also known as Fipronil.
Background and Prior Art
5-Amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl
sulfinyl pyrazole or 5-Amino-[2,6-dichloro-4-(trif]uoromethyl)phenyl]-4-[-(1 (R,S)-trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile also known as Fipronil 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. 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 to prepare, are very expensive and cannot be used on commercial scale. Many of these processes suffer from poor selectivity.
WO01/30760 describes oxidation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole with trifluoro-acetic acid and hydrogen peroxide in the presence of boric acid. The quantity

of trifluoroacetic acid used is 14.5 molar equivalents. The patent also
discloses the preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethyl
phenyl)-3-cyano-4-trifluoromethylthio-pyrazole from 5-amino-1-(2,6-
dichloro-4-trifluoromethyl phenyl)-3-cyano pyrazole-4-yl disulphide.
European Patent publication No.295117 describes the preparation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulphinyl pyrazole starting from 2,6-Dichloro-4-trifluoromethylaniline to give an intermediate 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole which is oxidized with meta-chloroperbenzoic acid in chloroform to give desired product.
Oxidizing agents such as perbenzoic acids do not provide effective and regioselective oxidation of electron deficient sulfides such as trifluoromethylsulphides which are less readily oxidized than other sulfides. Trifluoroacetic acid and trichloroacetic acid are found to be very efficient and regioselective oxidation medium for oxidation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole in presence of hydrogen peroxide. Trichloroacetic acid can not be used alone due to higher melting point. Trifluoroacetic acid on the other hand is very regioselective with respect to conversion and low by-products formation. However, 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.
W000/35851/2000 talks about synthesis of 2,6-Dichloro-4-trifluoromethylaniline starting from 3,4,5-trichloro-benzotrifluoride in the presence of alkaline fluorides like lithium fluoride and ammonia in the

presence of N-methylpyrrolidone at 250°C to give 97% conversion and 87% selectivity. The main drawback of the above process is the synthesis of 3,4,5-trichlorobenzotrifluoride in high yield and purity. Chlorination of p-chlorobenzotrifluoride gives a mixture of 3,4,5-trichlorobenzotrifluoride in 72% GLC conversions, 3,4-dichloro and tetrachlorobenzotrifluoride. The process to get pure 3,4,5-isomer from this mixture by fractionation followed by crystallization is very tedious. Moreover in-spite of using very pure intermediates, substantial amount of an undesired isomer (3-amino-4,5-dichlorobenzotrifluoride) is also obtained.
Another approach to generate 3,4,5-trichlorobenzotrifluoride with high yield and purity is to perform denitrochlorination of 4-chloro-3,5-dinitrobenzotrifluoride in the presence of a catalyst as described in GB Patent 2154581A. Even though the process produces 3,4,5-trichlorobenzotrifluoide in high yield and purity, the reaction conditions are too drastic to be employed for an industrial process.
The known commercial processes for the manufacture of Fipronil uses corrosive and expensive chemical such as trifluoroaceticacid, hydrogen peroxide and m-chloroperbenzoicacid Trifluoroacetic acid is expensive and generally not used in large quantities, as well as of m-chloroperbenzoic acid is difficult to handle at commercial scale due to its un-stability and detonating effect. Also the raw material used such as 2,6-Dichloro-4-trifluoromethylaniline are not easily available or made. The overall process for the Fipronil as disclosed above is found to be unsatisfactory in one respect or the other.

Thus, there is felt a need for preparing Fipronil from easily available raw materials in a simple and economical manner at an industrial level, with high yields and purity.
Object of the Invention
The main object of the invention is to provide a convenient and economically feasible process for preparing trifluoromethylsulfinyl pyrazole compound.
Another object of the present invention is to provide a process for preparing Fipronil using easily and commercially available raw materials.
Yet, another object of the present invention is to provide a process for preparing Fipronil in high yield and high purity.
Summary of the Invention
In accordance with the present invention there is provided a process for the preparation of a trifluoromethylsulfinyl pyrazole compound of formula I,

wherein, R1 and R2 contain elements of halogen group respectively;
and R3 is a perhaloalkyl said process comprising: a) halogenating an aromatic compound of formula II

wherein, R is a halogen and R3 is a perhaloalkyl, to obtain a polyhalogenated perhaloalkyl benzene compound of formula III;

wherein, R , R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl.
b) reacting in a polar solvent, the compound of formula III with anhydrous ammonia in the presence of an alkali halide at a temperature of about 200 °C to 300 °C and a pressure of about 20 to about 50 kg/cm2 to obtain a halo-perhaloalkyl aniline compound of formula IV;

wherein R2 is halogen and R3 is a perhaloalkyl.
c) reacting halo-perhaloalkylaniline compound of formula IV with a
halogenating agent in a solvent to obtain a product mixture containing
polyhalogenated perhaloalkylaniline compound of formula V;

wherein, R1 and R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl.
d) isolating polyhalogenated perhaloalkylaniline compound of formula V from
the product mixture;
e) diazotizing the isolated polyhalogenatedperhaloalkyl aniline compound of
formula V with nitrosyl sulfuric acid in the presence of an acid solvent to form
a diazotized derivative of compound V;

f) reacting the diazotized derivative of compound V with cyanoalkyl
propionate derivative and ammonia at a temperature range of about 0 C to
25°C to obtain a reacted mixture containing pyrazole compound of formula
VII;

wherein, R1 and R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl.
g) isolating the pyrazole compound of formula VII from the reacted mixture
with a halogenated aliphatic hydrocarbon solvent followed by evaporating the
solvent to yield crude pyrazole compound VII;
h) sulfenylating the crude pyrazole compound of formula VII with a sulfenylating agent in an halogenated aliphatic hydrocarbon solvent to obtain a product mixture containing thio pyrazole compound of formula IX

wherein, R1 and R2 contain elements of halogen group respectively;
and R3 is a perhaloalkyl. followed by isolating the thiopyrazole compound from the product mixture; and
i) oxidizing the isolated thio pyrazole compound of formula IX in a reaction medium comprising a oxidizing agent , a solvent system and a corrosion inhibitor to yield a product mixture containing trifluoromethyl sulfinyl pyrazole compound of formula I.
In preferred embodiment of the present invention R , R1 and R2 are chlorine, and R3 is trifluoromethyl .
The polar solvent used in step (b) is selected from a group selected from a group consisting of N-methyl pyrrolidone, dimethyl sulfone, N,N'-dimethylimidazolidinone and diphenyl sulfone.
Typically, the polar solvent is N-methyl pyrrolidone.

Typically, the alkali halide is potassium fluoride.
The reaction of compound of formula III with ammonia and alkali halide is carried at a temperature range of about 235°C to about 250°C and at a pressure of about 25 kg/cm2 to about 42 kg/cm2.
The halogenating agent used to halogenate compound IV is at least one selected from a group consisting of chlorine, sulfuryl chloride, thionyl chloride and phosphorus pentachloride.
Typically, the halogenating agent is sulfuryl chloride.
The halogenation is carried out in a solvent, particularly a chlorinated solvent selected from a group consisting of chloroform, dichloroethane, dichloromethane, chlorobenzene and o-dichlorobenzene.
Typically, the polyhalogenated perhaloalkylaniline compound of formula V is isolated from the product mixture by distillation.
In preferred embodiment of the present invention, the solvent system in oxidation step (i) is a mixture of at least two solvents selected from a group of halogenated solvents consisting of trifluoroaceticacid, trichloroaceticacid, dichloroaceticacid, chlorobenzene, dichloromethane and dichloroethane.
In accordance with one aspect of the present invention, the solvent system in step (i) is a mixture of trifluoroacetic acid and chlorobenzene in a ratio of 60:40% w/w to 55:45% w/w.

In accordance with yet another aspect of the present invention the solvent system in oxidation step (i) is a mixture of trifluoroacetic acid and trichloroacetic acid in a ratio of 20: 80% w/vv.
Typically, trifluoroacetic acid is used in the amount of 7 to 13.5 molar equivalents.
In accordance with another aspect of the present invention the solvent system in oxidation step (i) is a mixture of trichloroacetic acid and chlorobenzene in a
ratio of 80: 20% w/w.
In accordance with yet another aspect of the present invention the solvent system in oxidation step (i) is a mixture of trichloroacetic acid, dichloroacetic acid and chlorobenzene. The chlorobenzene content in the mixture ranges from 20% to 30%w/w.
Typically, trichloroaceticacid is used in the amount of 5 to 14 molar equivalents.
The oxidizing agent is a peroxide compound selected from the group consisting of hydrogen peroxide, tert-butyl hydrogen peroxide, benzoyl peroxide and sodium peroxide.
Typically, the oxidizing agent is hydrogen peroxide.

Typically, the amount of hydrogen peroxide used is about 0.8 moles to about 1.2 moles per mole of the compound of formula IX.
The corrosion inhibitor used during oxidation step (i) is boric acid.
The sulfenylating agent used in step (h) is trifluoromethyl sulfenyl chloride of formula VIII.
In preferred embodiment of the present invention, trifluoromethyl sulfmyl pyrazole compound I is further purified by at least one of the processes of crystallization and leaching.
The crystallization is carried out using at least one solvent selected from a group consisting of toluene, chlorobenzene and ethyl acetate.
In preferred embodiment of the present invention crystallized trifluoromethyl sulfinyl pyrazole compound I is further purified by leaching .
Typically, the leaching trifluoromethyl sulfinyl pyrazole compound I is carried out using at least one solvent selected from a group consisting of toluene, chlorobenzene and ethyl acetate .
In preferred embodiment of the present invention, the solvent mixture used for leaching is chlorobenzene and ethyl acetate. The chlorobenzene content in the mixture ranges from 5% to 100% v/v.

Typically, the chlorobenzene is in the ratio 2-10 parts per part of trifluoromethylsulfinyl pyrazole compound I.
Typically, the compound of formula II is 4-chlorobenzotriflouride.
The compound of formula III is 3,4-dichlorobenzotriflouride.
The compound of formula IV is 2-chloro-4-trifluormethylaniline.
The compound of formula V is 2,6-dichloro-4-trifluormethylaniline .
The cyanoalkyl propionate derivative is ethyl-2,3-dicyanopropionate of formula VI.
The compound of formula VII is 5-amino-3-cyano-l-(2,6-dichloro-4-triflouro
methyl phenyl)-pyrazole.
The compound of formula IX is 5-amino-[2,6-dichloro-4-(trifluoromethyl) phenyl]-4-[trifluoromethylsulfenyl]-lH-pyrazole-3-carbonitrile.
In preferred embodiment of the present invention the trifluoromethyl sulfinyl pyrazole compound of formula I is 5-amino-[2,6-dichloro-4-(trifluoromethyl)
phenyl]-4-[-(l(R,S)-trifluoro methyl) sulfinyl]-lH-pyrazole-3-carbonitrile.
Typically, the purity of 5-amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[-
(l(R,S)-trifluoromethyl)sulfmyl]-lH-pyrazole-3-carbonitrile is greater than 98%.

Detailed Description of the Invention
The process for trifluoromethyl sulfinyl pyrazole compound of formula I is illustrated with reaction sequence as depicted below in scheme 1.

Scheme I
In accordance with the present invention polyhalogenated perhaloalkyl benzene compound of formula III is manufactured in high yields and purity by chlorination of aromatic compound of formula II . In preferred embodiment of the present invention compound II is p-chlorobenzotrifluoride.

Ammonolysis of polyhalogenated perhaloalkyl benzene compound of formula III to obtain halo-perhaloalkylaniline compound of formula IV is easier and facile as compared to that of p-chlorobenzotrifluoride (compound II) and much higher conversions as compared to that of p-chlorobenzotrifluoride.
Polyhalogenated perhaloalkyl benzene compound of formula III is ammonolyzed with anhydrous ammonia in the presence of a solvent. Ammonolysis is conducted in the presence of alkali halides under pressure at 20 to 50 kg/cm2 and in a temperature range of about 200°C to about 300°C. Catalytic amounts of copper compound may be used during ammonolysis. The alkali halide is preferably potassium fluoride. Anhydrous ammonia is used in excess of 2-6 m/m to start with. As the reaction proceeds, more ammonia is fed to maintain the reactor pressure and to minimize side reactions, which predominate at higher temperature due to lowering of ammonia concentrations.
In a preferred embodiment of the present invention, the solvent employed in the present process can be any solvent or a mixture of solvent, which do not decompose under the reaction conditions and is inert with respect to the reactants. Preferably the solvent used is a polar solvent. The polar solvent is selected from a group consisting of N-methyl pyrrolidine, N,N'-dimethylimidazolidinone, diphenyl sulfone and dimethylsulfone. N-methylpyrrolidone is the solvent of choice as it does not interact with the reactants and at the same time it solubilises potassium fluoride.
Halo-perhaloalkylaniniline compound is further halogenated to polyhalogenated perhaloalkyl aniline compound of formula V, halogenation is

is carried out using atleast one of the halogenating agents selected from the group consisting of chlorine, thionyl chloride, sulfuryl chloride and PC15 at temperatures ranging between 0°C to 100°C, preferably 0°C to 70°C. The preferred halogenating agent is sulfuryl chloride. Among various halogens, the preferred halogen is chlorine unless a specific halogen is desired. The amount of halogenating agent used is limited to 10 to 50% excess, relative to the stoichiometric amount, preferably about 10-20% excess of the stoichiometric amount. Preferably, halogenation is done in chlorinated hydrocarbon solvents. The preferred solvents are chloroform, dichloroethane, dichloromethane, chlorobenzene and o-dichlorobenzene.
In preferred embodiment of the present invention, the compound of formula V is 2,6-dichloro-4-trifluoromethylaniline. It is further purified by fractional distillation of the product post halogenation. Distilled product can be crystallized from a suitable solvent to achieve the desired quality.
2,6-Dichloro-4-trifluoromethylaniline is diazotized with nitrosyl sulfuric acid in acid solvent and then treated with ethyl cyanopropionate compound and ammonia at a temperature ranging from 0 to 25 °C to give pyrazole derivative of formula VII, the pyrazole compound is further extracted from the reaction mixture by using halogenated aliphatic hydrocarbon. The solvent is then removed to isolate crude pyrazole.
In a preferred embodiment of the present invention, cyanoalkyl propionate derivative is ethyl-2,3-dicyanopropionate.

Crude pyrazole of formula VII is sulfenylated with a sulfenylating agent to give thiopyrazole compound of formula IX, the reaction is carried out in halogenated aliphatic hydrocarbon solvent. Thiopyrazole compound is further isolated by the distillation of the solvent.
In preferred embodiment of the present invention the sulfenylating agent is trifluoromethyl sulfenyl chloride.
Thiopyrazole compound of formula IX is then oxidized to trifloromethyl sulfmylpyrazole compound of formula I, the oxidation is carried out in medium containing a solvent and a oxidizing agent. The oxidizing agent is selected from a group consisting of hydrogen peroxide, tert-butyl hydrogen peroxide, benzoyl peroxide and sodium peroxide. Most preferred oxidizing agent is hydrogen peroxide. The oxidation is carried out in the presence of corrosion inhibitor such as boric acid. The amount of hydrogen peroxide used is about 1.05 moles to about 1.2 moles per mole of the compound of formula IX.
The solvent used for oxidation is a mixture of at least two solvents selected from a group consisting of trifluoroacetic, trichloroacetic acid, chlorobenzene, dichloromethane and dichloroethane.
In accordance with another aspect of the present invention the solvent system in oxidation step (i) is a mixture of trichloroacetic acid and chlorobenzene in a ratio of 80: 20% w/w.

In accordance with another aspect of the present invention the solvent system in step (i) is a mixture of trichloroaceticacid, dichloroaceticacid and chlorobenzene in a ratio of 70:30 - 80:20% w/w.
Typically, trichloroacetic acid is used in the amount of 5 to 14 molar equivalents.
In another aspect of the present invention oxidation is carried out using a mixture of trifluoroacetic acid and trichloroacetic acid in a ratio of 20: 80%
w/w.
In one aspect of the present invention oxidation is carried out using a mixture of trifluoroacetic acid and chlorobenzene in a ratio of 60:40% w/w to 55:45% w/w.
Total amount of the trifluoroacetic acid used is 7 to 13.5 molar equivalents.
The quantity of peroxide used depends on required optimal conversion with minimum by-product formation such as sulfone derivative.
In preferred embodiment of the present invention compound of formula IX is
5-Amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[-(-trifluoromethyl)
sulfenyl]-lH-pyrazo.le-3-carbonitrile.

In preferred embodiment of the present invention compound of formula I is
(5-Amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[-(l(R,S)-
trifluoromethyl)sulfmyl]-lH-pyrazole-3-carbonitrile).
Crude Fipronil (5-Amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[-(l(R,S)-trifluoromethyl)sulfinyl]-lH-pyrazole-3-carbonitrile), formula I thus formed is isolated by removing the solvent.
Crude Fipronil is further purified by crystallization using at least one solvent selected from a group consisting of esters of aliphatic acids and halogenated aromatic hydrocarbons, mainly ethylacetate and chlorobenzene. The solvent mixture is used depending upon the associated impurities present in fipronil. Crystallized fipronil is further subjected to leaching using a solvent and/or a mixture of solvents selected from chlorobenzene and ethyl acetate.. The fipronil thus obtained after crystallization and leaching has the purity of above 98%.
The invention is further illustrated with respect to the following examples which do not limit the scope of the invention in any way.
In the examples m/m means one gram mole of product obtained from one gram mole of substrate input.

Examples
Example- 1
1050 ml of N-methylpyrrolidone was charged in an autoclave along with 102 g (1 m/m) anhydrous activated potassium fluoride, 377 g (1.75 mole,) 3,4-dichlorobenzotrifluoride was added and a pressure pot was fitted to the autoclave. 158 g (5.3 m/m) ammonia gas was passed in the reactor from the pressure pot at ambient temperature. The content of the reactor was heated to 245-250°C over a period of 2 hours to get reactor pressure of 30-32 kg/cm2. Excess NH3 was fed from the pressure pot to maintain the reactor pressure at 38-40 kg/cm2 at 245-2500C liquid temperature. Reaction mixture was maintained at 245-250°C and at 38-40 kg/cm2 pressure for further 8 hours. Reaction mixture was cooled to ambient temperature, NH3 was vented and recovered. Reaction mixture on treatment and fractionation gave 77% yield of 2-chloro-4-trifluoromethylaniline and 13% yield of 2-chloro-5-trifluoro methyl aniline based on consumed 3,4-dichlorobenzotrifluoride.
Example- 2
815 ml on N-methylpyrrolidone was charged in an autoclave along with 291 g 3,4-dichlorobenzotrifluoride (1.35moles) and ll8g (1.5 m/m) of calcined potassium fluoride and a pressure pot was fitted to the autoclave. 213 g (9.2 m/m) of ammonia gas was fed into the pressure pot. 158 g (6.88 m/m) of ammonia gas was passed into the reactor from the pressure pot at ambient temperature initially and then the mixture in the autoclave was gradually heated to 245-250°C liquid temperature and further maintained at temperature .245-250°C and pressure 38-40 kg/cm2 for 6 hours by feeding ammonia gas to

maintain the desired reactor pressure. After fractionation the yield of 2-chloro-4-trifluoromethylaniline was 75.2% based on 3,4-dichlorobenzotrifluoride consumed.
Example -3
75.4 g (0.35 moles) of 3,4-dichlorobenzotrifluoride was added to 210 ml of N-methylpyrrolidone along with 30.45 g (0.525 m) of calcined potassium fluoride & 1.73 g cuprous chloride (0.0174m) in an autoclave. Ammonia (lmole) gas was passed & the resultant reaction mixture was heated to 235°C to get a pressure of 19 kg/cm . Ammonia gas was further fed to maintain the pressure of the resultant mixture at 25-26 kg/cm for 6 hrs at 235°C reaction temperature. After fractionation the yield of 2-chloro-4-trifluoromethyl aniline was 64% based on 3,4-dichlorobenzotrifluoride consumed.
Example -4
75.4 g (0.35 moles) of 3,4-dichlorobenzotrifluoride was added to 210 g of dimethylsulfone & 30.45 g (0.525 m) of calcined potassium fluoride in an autoclave. The ammonia gas (6-7 g (1-1.2 m/m)) was passed at 30°C. The resultant reaction mixture was heated to 235°C.The pressure was maintained at 25-26 kg/cm by feeding ammonia gas at regular interval of time. The reaction mixture was maintained for 6 hrs at the above temperature and pressure, was then cooled to 50°C & worked by filtration of the salt after venting and recovering ammonia followed by fractionating the mixture under reduced pressure. The yield of 2-chloro-4-trifluoromethylaniline was 84% based on 3,4-dichlorobenzotrifluoride consumed.

Example -5
75.4 g (0.35 m) of 3,4-dichlorobenzotrifluoride was added to 210 ml of N,N'-dimethylimidazolidinone along with 30.45 g (0.525 m) of calcined potassium fluoride in an autoclave Ammonia gas (1 m/m) was fed and the resultant reaction mixture was heated to 235°C to get a pressure of 19 kg/cm2. Ammonia gas was further fed to maintain the pressure of the resultant mixture at 25-26 kg/cm2 for further 6 hrs at 235°C After fractionation the yield of 2-chloro-4-trifluoromethyl aniline was 71.8% based on 3,4-dichlorobenzotrifluoride consumed.
Example- 6
A mixture (1.0 mole isomer mixture) (301 g) of 2-chloro-4-trifluoromethylaniline (0.88m), 2-chloro-5-trifluoromethylaniline (0.117m) and N-methyl pyrrolidone (NMP) (1.06 m/m) was mixed with 500 ml chlorobenzene. 148.4 g (1.1 m/m) of sulfuryl chloride was added to the mixture at 55-60°C over a period of 4 hours and the reaction mixture was maintained at 55-60°C for 4 hours. Reaction medium on treatment and fractionation gave 0.84 m of 2,6-dichloro-4-trifluoromethylaniline, 95% yield on 2-chloro-4-trifluoromethylaniline.
Example- 7
A mixture (276 g) of 2-chloro-4-trifluoromethylaniline (0.854 m), 2-chloro-5-trifluoromethylaniline (0.147 m) and NMP (0.73 m/m) was mixed with 500 ml chlorobenzene. 135 g (1 m) sulfuryl chloride was added to the mixture at 55-60°C liquid temperature over a period of 4 hours and the reaction temperature was maintained for further 2 hours. Additional 20.2 g (0.15 m/m) of sulfuryl chloride was added for completion of reaction. Reaction medium

on treatment and fractionation gave 0.809 m of 2,6-dichloro-4-trifluoromethylaniline, 94% yield on 2-chloro-4-trifluoromethylaniline.
Example-8
A mixture (740 g) (2.68m) containing 2-chloro-4-trifluoromethyaniline (2.346m), 2-chloro-5-trifmoromethylaniline (0.334m) and NMP (0.686 m/m) was charged with 400 ml dichloroethane in to the reactor. It was then reacted with 430 g (3.18m) of sulfuryl chloride at 55-60 °C over a period of 4 hrs & further maintained at 65-70°C for 2 hrs. The reaction mixture was worked up by adding water & treating with 5N NaOH, the organic layer was fractionated under reduced pressure over a 5 feet column to get 504.9 g of distilled 2,6-dichloro-4-trifluoromethylaniline. The yield of 2,6-dichloro-4-trifluoromethyl aniline was 93.5% on 2-chloro-4-trifluoromethylaniline.
Example-9
A mixture (0.99 m) (270g) containing 2-chloro-4-trifluoromethyl aniline (0.82 m), 2-chloro-5-trifluoromethylaniline (0.174 m) and NMP (0.676 m/m) was mixed with 210 ml chlorobenzene. It was chlorinated by passing 1.22m chlorine gas at 50-55°C over a period of 8 hrs. The reaction mixture was worked up by adding water, treating the organic layer with 5N NaOH and the organic layer was fractionated under reduced pressure over 3 feet column to get 92.5 g distilled 2,6-dichloro-4-trifluoromethylaniline. Yield was 49 % on 2-chloro-4-trifluoromethylaniline.

Example 10
Sodium 38.6 g (1.68 m) was dissolved in ethanol 500 ml. The obtained sodium ethoxide solution was added to 201 g (1.76 m) of ethyl cyanoacetate over 0.5 hour to get a slurry of sodium salt of ethyl cyanoacetate. The above slurry was added to 107 g (1.77 m) of glycolonitrile in 330 ml ethanol at 5-10°C over 3 hours. The addition of slurry of sodium salt of ethyl cyanoacetate to glycolonitrile resulted in clear solution with the liberation of heat. The solution was stirred at 5-10°C for additional 1 hour and then raised the liquid temperature to 30°C-and equilibrated for 4 hours. The mixture was then cooled to 5-10°C and neutralized to pH = 4.45. The reaction mass was further equilibrated for 1 hour. The mixture was filtered at 10°C and washed the cake with ethanol. The Filtrate and wash were combined and ethanol was distilled under vacuum, the crude 2,3-dicyano-ethyl propionate thus obtained was dissolved in dichloromethane and the solution was washed with cold water followed by 10% soda ash solution. The organic layer containing 2,3-dicyanoethyl propionate was dried over magnesium sulphate. The oily layer obtained after removal of dichloromethane was distilled under reduced pressure over a column to give ethyI-2,3-dicyanopropionate in 79.6% yield.
Example 11
Preparation of 5-aminopyrazole (VII):
To 2,6-dichloro-4-trifluoromethyl aniline 230 g and acetic acid 150 ml was added nitrosyl sulphuric acid (prepared from 286 g sulphuric acid 98%, water 150 ml, 98% nitric acid 65g and sulphur dioxide 64 g) over one hour at 30°C and maintain at 30°C for one more hour. Heat the mass to 50-55°C over 1/2 hour and the absence of 2,6-dichloro-4-trifluoromethyl aniline was

monitored. Cool the mass to 30°C, and the excess nitrosyl sulphuric acid was destroyed.
The above diazotized mass was added to a mixture of 250 ml of acetic acid, 162 g ethyl-2,3-dicyanoproprionate and 425 ml water over 4-5 hours maintaining temperature 0-5°C. Further maintain at 0°C / 2 hours, 5°C / 1 hour, 10°C / lhour, 15°C / 1 hour. Add 800 ml water at 15°C over V2 hour, extract the solution with 3x250 ml methylene dichloride. Separate layers. Wash dichloromethane layer with 250 ml water, cool the dichloromethane layer to 0°C and wash with 250 ml 8N aq. NH3 under stirring for one hour. Separate layers, take dichloromethane layer, pass NH3 gas at 0-5°C till free NH3 is observed on top of the condenser and maintain the reaction mass for 3-4 hours at 0-5°C. Then add 250 ml water, stir for 1/2 hour, separate layers, extract aq. layer with 2x100 ml dichloromethane, dry dichloromethane layer with MgS04, concentrate dichloromethane layer to dryness, the yield of 5-amino pyrazole is 288 g, and the purity is 95-98%.
Example 12
To a glass reactor having a central vertical stirrer, a vertical condenser & a dip
tube for passing C12, was charged 730ml of 3N HC1. To this Carbon disulfide
83.4gm was added followed by 388gm C12 gas bubbled over l0hrs at 24-
25°C. Reaction was monitored by GLC & terminated when CS2 was 198gm of the product, trichlorornethylsulfenylchloride, with 93% purity was
isolated by layer separation. It was purified by fractionation to give 194gm
product, with 95% purity.
Trichloromethylsulfenylchloride (194 gm) was added in to a mixture of
500gm water & 100ml methylene dichloride, along with 83gm Sulfur dioxide

gas at 10°C, over a period of 4 hrs. Reaction was terminated, when
trichloromethyi sulfenyl chloride was Thiophosgene with 45% purity was isolated by layer separation, 228 gms of
thiophosgene was obtained, which was added in to 175gm activated KF,
110gm ortho-chlorobenzyl chloride, 340gm spherogel (with 2mm diameter),
at 60°C, over a period of 3hrs & further maintained at 60°C for 2hrs.
Conversion was 98% and 138gms O-chlorobenzyl trifluoromethylsulfide was
isolated by filtration, followed by distillation. O-
chlorobenzyltrifluoromethylsulfide was added to 500ml methylene chloride, cooled to 10°C & 41gm Cl2 was bubbled into it, the reaction was maintained for 2 hrs & then heated slowly to 40-45 °C, generated trifluoromethylsulfenyl chloride was passed in 5-amino-3-cyano-l-(2,6-dichloro-4-trifluorornethyl phenyl)-pyrazole, the reaction was carried out in halogenated aliphatic hydrocarbon solvent to get 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole. Yield of thiopyrazole was 90%.
Example 13
A solvent mixture (180 g) (trifluoroacetic acid:ichlorobenzene, 60:40%w/w) containing trifluoroacetic acid (TFA) (108 g) and chlorobenzene (72 g) was charged in a reactor. To this 50.6 g (0.12m) of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole was added and the mixture was cooled to 10-12°C. Then boric acid (0.60 g) was added to above cooled 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 % with Example 14
A solvent mixture (104 g) (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. The reaction 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 and trifluoroacetic acid was vacuum distilled. The reaction mixture was worked up as above by adding chlorobenzene, methanol and neutralizing the mixture with aqueous NaHC03 and filtration to yield 32.9 g (88% yield) crude Fipronil of purity 93.2 %.
Example 15
A solvent mixture (300 g) containing trichloroacetic acid (240 g) and trifluoroacetic acid (60 g) was charged in a reactor followed by addition of boric acid (1 g) and the reaction mass was stirred at 30°C. To this reaction

mass, 84.5g (0.20m) of 5-amino-l-(2,6-dichloro-4-trifluoromethyl phenyl)-3-cyano-4-trifluoromethyl thiopyrazole was added and the resultant mixture was cooled to 15°C. 15.48 g (0.23 m) of 50.5 % aqueous hydrogen peroxide was added in lots over 1.5 hours to the above mixture and was further stirred at 15 °C for 16 hours to get 91 % Fipronil .The reaction mixture was worked up by adding 240 ml chlorobenzene and water. After work up as above, 69.2 g (76 %) of crude Fipronil of purity 96.5 % was obtained.
Example 16
In to a mixture of 1200 gms of Trichloroacetic acid, 300 gms of chlorobenzene, 2 gms boric acid, added 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole 421 gms and cooled the content to 15- 20°C. 68 g (1.0 m) of 50 % aq. H202 was added and mass was stirred for 20 hrs. After work up as above, 418g (90 %) of crude Fipronil of purity 94 % was obtained .The filtered Fipronil was then purified using chlorobenzene (4 ml/g) followed by mixture (1 ml/g, 80:20 v/v) of Ethyl acetate and chlorobenzene to get 371 gms (85%) of Fipronil of greater than 97% purity.
Example 17
A mixture of 700 gms of dichloroacetic acid and trichloroacetic acid was taken along with 300 gms of chlorobenzene, 2 gms boric acid and 280 gms of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl thiopyrazole, the content were cooled to 15 - 20°C. 44.2 g (0.65 m) of 50 % aq. H202 was added and mass was stirred for 20 hrs. The mass was then processed and Fipronil was isolated by filtration. After work up as above, 269g (87 %) of crude Fipronil of purity 94 % was obtained. The filtered

Fipronil was then purified using chlorobenzene (5 ml/g) followed by mixture (1 ml/g, 80:20 v/v) of Ethyl acetate and chlorobenzene to get 232 gms (80%) of Fipronil of greater than 97 % purity.
Example 18 : Purification of fipronil
The above fipronil of purity 97% was treated with a mixture (1 ml/mg) of ethylacetate & chlorobenzene (80:20 v/v). This reaction mixture was heated to 85-90°C & maintained for lhr. It was further cooled up to 30°C in stages & filtered. Fipronil thus obtained had a purity of 98%. This cycle was repeated to obtain fipronil of above 98% purity.
The useful constituents from various streams of crystallization, leaching as above were reused and recycled, fipronil was isolated in 80-85% yield with purity of above 98%.
The numerical values of various parameters given in the specification are but approximations and slightly higher or slightly lower values of these parameters fall within the ambit and the scope of the invention.
While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be highly 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 disclosures 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 trifluoromethylsulfinylpyrazole compound of formula I,

said process comprising:
a) halogenating a aromatic compound of formula II

wherein, R is a halogen and R3 is a perhaloalkyl, to obtain a polyhalogenated perhaloalkyl benzene compound of formula III;

wherein, R ,R2 contain elements of halogen group respectively; and R3
is a perhaloalkyl,
b) reacting in a polar solvent, the compound of formula III with anhydrous
ammonia in the presence of an alkali halide at a temperature of about 200 °C
to 300 °C and a pressure of about 20 to about 50 kg/cm2 to obtain a halo-
perhaloalkyl aniline compound of formula IV;

wherein R2 is halogen and R3 is a perhaloalkyl,
c) reacting halo-perhaloalkylaniline compound of formula IV with a
halogenating agent in a solvent to obtain a product mixture containing
polyhalogenated perhaloalkylaniline compound of formula V;

wherein, R1and R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl,
d) isolating polyhalogenated perhaloalkylaniline compound of formula V from the product mixture;
e) diazotizing the isolated polyhalogenated aniline compound of formula V with nitrosyl sulfuric acid in the presence of an acid solvent to form a diazotized derivative of compound V;
f) reacting the diazotized derivative of compound V with cyanoalkyl propionate derivative and ammonia at a temperature range of about 0°C to 25 °C to obtain a reacted mixture containing pyrazole compound of formula VII;

wherein, R1 and R2 contain elements of halogen group respectively; and R3 is a perhaloalkyl,

g) isolating the pyrazole compound of formula VII from the reacted mixture with a halogenated aliphatic hydrocarbon solvent followed by evaporating the solvent to yield crude pyrazole compound VII;
h) sulfenylating the crude pyrazole compound VII with a sulfenylating agent in a halogenated aliphatic hydrocarbon solvent to obtain a product mixture containing thio pyrazole compound of formula IX

wherein, R1 and R2 contain elements of halogen group respectively;
and R3 is a perhaloalkyl, followed by isolating the thiopyrazole compound form the product mixture; and
i) oxidizing the isolated thio pyrazole compound of formula IX in a reaction medium comprising a oxidizing agent , a solvent system and a corrosion inhibitor to yield a product mixture containing trifluoromethyl sulfinyl pyrazole compound of formula I.
2. The process as claimed in claim 1, wherein R, R1 and R2 are chlorine and R3 is trifluoromethyl.

3. The process as claimed in claim 1, wherein the polar solvent is selected from a group selected from a group consisting of N-methyl pyrrolidone, dimethyl sulfone,N,N'-dimethylimidazolidinone and diphenyl sulfone.
4. The process as claimed in any one of the preceding claims wherein the solvent is N-methyl pyrrolidone.
5. The process as claimed in claim 1, wherein the alkali halide is potassium fluoride.
6. The process as claimed in claim 1, wherein the reaction in step (b) is carried at a temperature range of about 235° C to about 250° C.
7. The process as claimed in claim 1, wherein the reaction in step (b) is carried at a pressure of about 25 kg/cm to about 42kg/cm.
8. The process as claimed in claim 1, wherein the halogenating agent used in step (c) is atleast one selected from a group consisting of chlorine, sulfuryl chloride, thionyl chloride and phosphorus pentachloride.
9. The process as claimed in claim 1, wherein the halogenating agent is sulfuryl chloride.
10. The process as claimed in claim 1, wherein the solvent in step (c ) is a
chlorinated solvent selected from a group consisting of, chloroform,
dichloroethane, dichloromethane, chlorobenzene and o-dichlorobenzene.

11. The process as claimed in claim 1, wherein the polyhalogenated
perhaloalkylaniline compound of formula V is isolated from the product
mixture by fractional distillation .
12. The process as claimed in claim 1, wherein the solvent system in step (i) comprises at least two solvents selected from a group of halogenated solvents consisting of trifluoroaceticacid, trichloroaceticacid, dichloroaceticacid chlorobenzene, dichloromethane and dichloroethane.
13. The process as claimed in claim 1, wherein the solvent system in step (i) is a mixture of trifluoroacetic acid and chlorobenzene in a ratio of 60:40%
w/w to 55:45% w/w.
14. The process as claimed in claim 1, wherein the solvent system in step (i)
is a mixture of trifluoroacetic acid and trichloroacetic acid in a ratio of 20:
80% w/w.
15. The process as claimed in any one of the preceding claims, wherein the amount of the trifluoroacetic acid is 7 to 13.5 molar equivalents.
16. The process as claimed in claim 1, wherein the solvent system in step (i) is a mixture of trichloroaceticacid , dichloroaceticacid and chlorobenzene .
17. The process as claimed in claim 16, wherein the chlorobenzene content in the mixture is about 20% to 30%w/w.

18. The process as claimed in claim 1, wherein the solvent system in step (i) is a mixture of trichloroacetic acid and chlorobenzene in a ratio of 80:20 w/w.
19. The process as claimed in any one of the preceding claims, wherein the amount of the trichloroacetic acid is 5 to 14 molar equivalents.
20. 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.
21. The process as claimed in any one of the preceding claims, wherein the oxidizing agent is hydrogen peroxide.
22. The process as claimed in any one of the preceding claims, wherein the amount of hydrogen peroxide used is about 0.8 moles to about 1.2 moles per mole of the compound of formula IX.
23. The process as claimed in claim 1, wherein the corrosion inhibitor is boric acid.
24. The process as claimed in claim 1, wherein the oxidation is carried out at a temperature 10 °C to 30 °C.
25. The process as claimed in claim 1, wherein the sulfenylating agent is trifluoromethyl sulfenyl chloride.

26. The process as claimed as claimed in claim 1, wherein the compound of formula II is 4-chlorobenzotriflouride.
27. The process as claimed as claimed in claim 1, wherein the compound of formula III is 3,4-dichlorobenzotriflouride.
28. The process as claimed as claimed in claim 1, wherein the compound of formula IV is 2-chloro-4-trifluormethylaniline.
29. The process as claimed as claimed in claim 1, wherein the compound of formula V is 2,6-dichloro-4-trifluormethylaniline .
30. The process as claimed as claimed in claim 1, wherein the cyanoalkyl propionate derivative is ethyl-2,3-dicyanopropionate.
31. The process as claimed as claimed in claim 1, wherein the compound of formula VII is 5-amino-3-cyano-l-(2,6-dichloro-4-triflouromethyl phenyl)-
pyrazole.
32. The process as claimed as claimed in claim 1, wherein the compound of formula IX is 5-amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[trifluoromethyl sulfenyl]-lH-pyrazole-3-carbonitrile.
33. The process as claimed in claim 1 further comprises the step of purifying trifluoromethyl sulfinyl pyrazole compound I by at least one process selected from the process consisting of crystallization and leaching.

34. The process as claimed in claim 33, wherein the crystallization of trifluoromethyl sulfinyl pyrazole compound I is carried out using at least one solvent selected from a group consisting of toluene, chlorobenzene and ethyl acetate.
35. The process as claimed in any one of the preceding claim further comprises purification of crystallized trifluoromethyl sulfinylpyrazole compound I by leaching.
36. The process as claimed in any one of the preceding claim, wherein the leaching of trifluoromethyl sulfinyl pyrazole compound I is carried out using at least one solvent selected from a group consisting of toluene, chlorobenzene and ethyl acetate.
37. The process as -claimed in any one of the preceding claim, wherein the solvent for leaching trifluoromethylsulfinylpyrazole compound I is a mixture of chlorobenzene and ethyl acetate.
38. The process as claimed in claim 37, wherein the chlorobenzene content in the mixture ranges from 5% to 100% v/v.
39. The process as claimed in claim 36, wherein the chlorobenzene is in the ratio of 2-10 parts per part of trifluoromethylsulfinyl pyrazole compound I.
40. The process as claimed in claim 36, wherein the chlorobenzene is in the ratio of 3-4 parts per part of trifluoromethyl sulfinyl pyrazole compound I.

41. A compound 5-amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[-
(l(R,S)-trifluoro methyl) sulfinyl]-lH-pyrazole-3-carbonitrile of formula I
made in accordance with the process as claimed in any one of the preceding
claims.
42. The process as claimed in any one of the preceding claim, wherein the
purity of 5-amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[-(l(R,S)-
trifluoro methyl) sulfinyl]-lH-pyrazole-3-carbonitrile is greater than 98%.

Documents:

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Patent Number

271132

Indian Patent Application Number

552/MUM/2010

PG Journal Number

06/2016

Publication Date

05-Feb-2016

Grant Date

03-Feb-2016

Date of Filing

03-Mar-2010

Name of Patentee

GHARDA KEKI HORMUSJI

Applicant Address

GHARDA HOUSE, 48 HILL ROAD, BANDRA(West), MUMBAI 400 050, MAHARASHTRA, INDIA

Inventors:

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

PCT International Classification Number

C07C209/00, C07C209/10, C07C211/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA