Title of Invention	PROCESS FOR THE PREPARATION OF A TRIFLUOROMETHYLTHIOETHER
Abstract	A process for the preparation of a trifluoromethylthioether of the formula (I) by reaction of a thiocyanate of the formula (II) with a trifluromethyl halide in the presence of a reducing system comprising a dithionite salt or a hydroxymethansulfinate salt or comprising one 15 or more reducing agents with sulphur dioxide.

Full Text

Process for the preparation of a trifluoromethylthioether. The present invention relates to a process for the preparation of a trifluoromethyl thioether of the formula (I) by reaction of a thiocyanate of formula (II) with a trifluromethyl halide in the presence a reducing system comprising a dithionite salt or a hydroxymethansulfinate salt or comprising one or more reducing agents with sulphur dioxide. Background Several methods are known for the preparation of perfluoroalkylthioethers including the compound (I). Preparation from perfluoroalkyl halides and disulphides has been described in the prior art: In United States patent no. 5,082,945 a process is described using a perfluoroalkyl halide which is brought into contact with a disulphide in the presence of a reducing agent consisting of a metal chosen among zinc, cadmium, aluminium and manganese, with sulphur dioxide or consisting of an alkali metal dithionite or of an alkali or alkali-earth metal or metal hydroxymethanesulphinate or consisting of a formate anion and sulphur dioxide. International' patent application no. WO 01/30760-A1 describes a similar method. European patent application no. 295117-A1 describes the use of sodium dithionite or.sodium borohydride in an aqueous-organic solvent such as ethanol or a mixture of alcohol and water. The previous mentioned methods are also described by Clavel et al. in Phosphorus, Sulfur and Silicon and the Related Elements (1991), 59(1-4), 423-6; Journal of the Chemical Society, Chemical Communications (1991), (15), 993-4 and Journal of the Chemical Society, Perkin Transactions 1 (1992), (24), 3371-5. In International patent application no. WO 02/066423-A1 a process is described utilising hydrazine and/or a metal borohydride as the reducing agent. Indeed it would be an advantage to utilise the compound (II) directly without having to prepare at first a disulphide from a thiocyanate compound of formula (It) prior to the preparation of the compound of formula (I) as is the case in the above references. Tordeux et al. in Journal of Fluorine Chemistry, 43(1989), 27-34, describes a process for the preparation of perfluoroalkylsulfides by reaction of a thiocyanate and a perfluoroalkylhalide in the presence of zinc. Moderate yields are reported using perfluorobutyl- or perfluorooctyHodide. However, poor yields are i observed using trifluoromethyl bromide. In European patent application no. 295117-A1 it is suggested to perform the reaction in the presence of a base or a reducing agent preferably sodium borohydride. The yield using a compound of formula (II), methyl iodide and potassium hydroxide is moderate (example 15). In the same application it is suggested to use an organometallic reagent such as a Grignard reagent. Again, using a compound of formula (II) and tert-butylmagnesium chloride a low yield is observed (example 16). Further, the handling of Grignard like reagents are difficult on a large scale, and a trifluromethylinagnesium halide is not easily prepared. Langlois et al. in Tetrahedron Letters 38(1997), 65-68, describes the preparation of trifluoromethyl sulfides from thiocyantes using trifluoromethyl trimethylsilane in the presence of tetrabutylammonium fluoride (TBAF). Both reagents are expensive and as such not desirable to use on a commercial scale and from the results it is seen that yields decreases significantly when using substituted aromatic thiocyantes compared to simple aromates and straight alkane substrates. In United States patent no. 5,756,849 benzyl thiocyanate is brought into contact with the potassium salt of triflouroacetic acid yielding 36% of benzyl trifluoromethyl sulfide. A process using benzyl thiocyanate as the starting material for the preparation of benzyl trifluoromethyl sulfide and involves the use of a pyridine-hydrofluoric acid complex for the exchange of three chlorine atoms with fluoro atoms is found in US patent no. 6,316,636. Although yields are high, the use of hydrofluoric acid does comprise a severe hazard. Despite of the recent progresses within the area there still exists a need for alternative processes for the manufacture of the compound having the formula (I) directly from the compound (II) in high yields using easily accessible materials and avoiding complicated and costly extra intermediate process steps. The compound (I) is a well known compound, which is useful as the starting material in the preparation of the insecticide Fipronil and related compounds by known methods, e.g. as described in European patent no. 295117-A1. The compound (II) is also a well known compound, which may be prepared according to well known procedures e.g. as disclosed in EP 295 117 Al. Description of the invention The present invention relates to a process for the preparation of a trifluoromethyl thioether of the formula (I) which is 5-amino-3-cyano-1 -(2J6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylthio-lif-pyrazole, said process comprising the step of reacting in a solvent a thiocyanate compound of the formula (II) which is 5-Amino-l-(2,6-dichloro»4-trifluoromethyl-phenyl)-4-thiocyanato-1H pyrazole-3-carbonitrile, with a trifluoromethylhalide in the presence of a reducing system comprising a dithionite salt or a hydroxymethansulfinate salt or comprising one or more reducing agents with sulphur dioxide. The trifluoromethylhalide may be chosen among CF3C1, CF3I and CF3Br. From an economical point of view the preferred choice is CF3Br. The molar ratio of trifluoromethylhalide to thiocyanate of formula (II) is preferably higher than 1. When the reducing system comprising a dithionite salt or a hydroxymethansulfinate salt is employed the amount of salt compound used is generally 1-15 molar equivalents relative to the thiocyanate of formula (II), preferably 2-11 molar equivalents. The salt compound is introduced into the reaction vessel either in solid form or dissolved/suspended in a solvent, preferably the same as the reaction solvent. The dithionite salt is preferably a metal or amine salt, such as sodium, potassium, calcium or ammonium with sodium dithionite being most preferred. The hydroxymethansulfinate salt is preferably a metal salt such as sodium (known as Rongalite) or zinc (known as Decroline) with sodium hydroxymethansulfinate being most preferred. When . employing the reducing system comprising sulphur dioxide and a reducing agent the reducing agent(s) is by example chosen between metals such as zinc, cadmium, aluminium and manganese; hydrazine; formic acid, salts of formate such as metal or amine salts, preferred are alkali metal or ammonium salts of formate and even more preferably the sodium or potassium salt of formate with sodium formate being most preferred; aluminium hydrides e.g. those of formulae R3R4A1H3 M[R3R4A1H2] or MAIH4, wherein R3 and R4 each independently of the other represents CM alkyl, and M is lithium or sodium and include (i-C4H9)2 A1H and L1AIH4; borohydrides e.g. metal or amine borohydrids such as NaBHU, LiBH4, (CH3)4NBH4, NaBH3CN; compounds of the formula (SI) wherein X represents O or S; Y1 and Y2, which may be identical or different, each represent H or O-R, where R represents a hydrogen atom, a linear or branched alkyl chain of 1-5 carbon atoms or an alkali metal atom; with the provisio that at least one of Y1 and Y2 is other than a hydrogen atom. Preferred are those where X represent O. More preferred are those where Y1 represents H or OH; and Y2 represent OH or O-alkali metal, with sodium being the preferred alkali metal. Even more preferred are phosphorous acid (H3PO3), hypophosphorous acid (H3PO2) and sodium hypophosphorous acid (NaH2PO2), with hypophosphorous acid and sodium hypophosphorous acid being the most preferred choice. Its is to be understood that the reducing agent of formula (HI) may be employed in one or more of its hydrated forms, preferably such as sodium hypophosphorous acid monohydrate (NaH2PO2, IH2O) and sodium hypophosphorous acid hydrate (NaH2PO2, XH2O) with sodium hypophosphorous acid hydrate being most preferred. The amount of reducing agent used is generally 1-15 molar equivalents relative to the thiocyanate of formula (II), preferably 2-11 molar equivalents. The reducing agent(s) is introduced into the reaction vessel as is e.g. either in solid or liquid form or dissolved/suspended in a solvent, preferably the same as the reaction solvent or water. The reducing agent(s) may be introduced portion wise, continuously or prior to the reaction and one may introduce the agent(s) as the last reagent to the reaction mixture. The sulphur dioxide may be present in a catalytic quantity but amounts higher than 1 equivalent relative to the thiocyanate of formula (II) is preferred, more preferably between 1-7 and even more preferably between 1.5 - 4.5 although the upper limit is not critical. The sulphur dioxide is added portion wise, continuously or prior to the reaction and one may introduce the sulphur dioxide as the last reagent to the reaction mixture. The sulphur dioxide is introduced to the reaction vessel either in gaseous form or dissolved in a solvent, preferably the same as the reaction solvent. The solvent for the reaction may in principle be any solvent that is inert and which is capable of dissolving the reactants under the reaction conditions. In this connection the term "inert" is intended to mean that the solvent does not in a substantial degree react with the components of the mixture. Preferably the solvent is a polar solvent such as formamide, pyridine, dimethylformamide (DMF), N,N-dimethylacetamide (DMA), Hexamethylphosphoric triamide (HMPT), N-methylpyrrolidone "(NMP), dimethyl sulphoxide (DMSO), . sulpholane and ethers such as dimethyl ether, dioxane, tetrahydrofuran and dimethoxyethane (DME) or mixtures thereof with DMF being the preferred choice. Small amounts of water maybe added to the solvent, e.g. a volume of up to 35% of the volume of solvent(s) used, and preferably in an amount of 5-30%. The reaction temperature is usually within the range of 20-110°C or at or below the boiling temperature of the solvent, preferably between 30-80°C, and even more preferably between 40-60°C. Due to the gaseous nature of the trifluoromethylhalide the reaction is performed under pressure in a suitable apparatus made of a non-reactive material e.g. a glass reactor or teflon coated reactor. A pressure of between 1 and 30 bars is preferred. Variation of the pH in the reaction mixture may be achieved by adding a buffer prior to or during the reaction. Examples of such buffer can be of the organic or inorganic type and include pyridine, amines (e.g. aqueous ammonia, triethylamine), alkali metal hydroxides and salts of weak acids such as alkali metal salts of carbonates, phosphates, sulphites, citrates and acetates (e.g. NaHCO3, Na2CO3, NaH2PO4, Na2HPO4, NaHSO3). At the end of the reaction the solvent(s) and the reaction products are separated and the trifluoromethyl thioether, compound (I), purified prior to any subsequent synthesis sequence. • The invention is illustrated by the following examples, which are not intended to limit the invention in any way but are only provided for illustratory purposes: Example 1.1 To a 200 ml Teflon insert to a Berghof autoclave was added 5-Amino-l-(2,6- dichloro-4-trifluoromethyl-phenyl)-4-thiocyanato-1H-pyrazole-3-carbonitrile (14.3 mmol 5.04g), and sodium formate (71.5 mmol 5.01g) and sulphur dioxide (43 mmol 2.75g) dissolved in a mixture of 50 ml DMF and 5 ml water. The autoclave was closed and with stirring for 5 minutes at room temperature, the autoclave was pressurized with CF3Br until the pressure was 11.5 bars. A total amount of 34.1 g of CF3Br was added. Then the autoclave was heated to 50°C for 3.5 hours. The autoclave was cooled to room temperature and opened after release of pressure. After washing with water and extracting the product with methyl-t-butylether the product was analyzed (GC internal standard method). Yield of 5-amino-3-cyano-l-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylthio-lH-pyrazole was 4.7g (78% of theory). A series of experiments using the above method is provided in Table 1. Example 2.1 , . . To a 50 ml Teflon insert to a Berghof autoclave was added 5-Amino-l-(2?6* dichloro-4-trifluoromethyl-phenyl)-4-thiocyanato-lH-pyrazole-3-carbonitrile (2.86 mmol 1.08g), and sodium formate (20 mmol 1.40g) and sulphur dioxide (5.94 mmol O.38g) dissolved in a mixture of 10 ml DMF and 2.8 ml water. Then the Teflon insert was cooled to -60°C, CF3Br (58 mmol 8.7g) condensed into the insert and the autoclave closed and heated to 55°C for 3 hours. The autoclave was cooled to room temperature and opened after release of pressure. After washing with water and extracting the product with methyl-t-butylether the product was analyzed (GC internal standard method). Yield- of 5-amino-3-cyano-l-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylthio-1H-pyrazole was 1.05g (87%). A series of experiments using the above method is provided in Table 2. Example 3.1 To a 50 ml Teflon insert to a Berghof autoclave was added 10 ml DMF with 2.8 g water, 5-Amino-l-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-thiocyanato-1H pyrazole-3-carbonitrile (2.88 mmol 1.104g), sodium dithionite (4.32 mmol 0.886g ) and Na2HPO4,12H2O (1.54g). The teflon insert was cooled to -60°C, CF3Br (58 mmol 8.7g) condensed into the insert and the autoclave closed and heated to 45°C for 3 hours. The autoclave was cooled to room temperature and opened after release of pressure. After washing with water and extracting the product with methyl-t-butylether the product was analyzed (GC internal standard method). Yield of 5-amino-3-cyano-l-(2,6-dichloro-4-trifluoromethyl- phenyl)-4-trifluoromethylthio-1H-pyrazole was 62%. Example 3.2 To a 50 ml Teflon insert to a Berghof autoclave was added 10 ml DMF with 2.7 g water, 5-Amino-l-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-thiocyanato-1H pyrazole-3-carbonitrile (1.106g) and Rongalite (4.29g). The teflon insert was cooled to -60°C, CF3Br (6.58g) condensed into the insert and the autoclave closed and heated to 45°C for 3 hours. The autoclave was cooled to room temperature and opened after release of pressure. After washing with water and extracting the product with methyl-t-butylether the product was analyzed (GC internal standard method). Yield of 5-amino-3-cyano-l-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylthio-1H-pyrazole was 41%. Example 4.1 14.5 mmol (5.52g) of 5-Amino-l-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-thiocyanato-lH-pyrazole-3-carbonitrile was added to a mixture of 50 ml of DMF and 37.5 mmol (2.4g) sulphur dioxide in a teflon lined autoclave at room temperature. The reactor was sealed and purged with nitrogen for 2 minutes followed by addition of CF3Br (16.8g). The reactor was heated to 30°C and 7.0g sodium formate dissolved in lOg of water added slowly during a 80 minutes period with maintenance of the temperature between 50°C and 54°C during the addition and for a further 60 minute period. The autoclave was cooled to room temperature and opened after release of pressure. After washing with water and extracting the product with methyl-t-butylether the product was analyzed (GC internal standard method). Yield of 5-amino-3-cyano-l-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylthio-1H-pyrazole was 84.7%. Example 5.1 14.5 mmol (5.52g) of 5-Amino-l-(2,6-dichloro-4"trifluoromethyl-phenyl)-4-thiocyanato-1H-pyrazole-3~carbonitrile and 63 mmol (6.67 g) sodium carbonate was added to a mixture of 50 ml of DMF and 37.5 mmol (2.4g) sulphur dioxide in a teflon lined autoclave at room temperature. The reactor was sealed and purged with nitrogen for 2 minutes followed by addition of CF3Br (16.8g). The reactor was heated to 30°C and 132 mmol (6.07g) formic acid dissolved in 10. ml of DMF was added slowly during a 45 minutes period with maintenance of the temperature between 55°C and 60°C during the addition and for a further 60 minute period. The autoclave was cooled to room temperature and opened after release of pressure. After washing with water and extracting the product with methyl-t-butylether the product was analyzed (GC internal standard method). Yield of 5-amino-3-cyano-l-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylthio-lH-pyrazole was 76.5%. Example 6.1 100 mmol 5-Amino-l-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-thiocyanato-1H-pyrazole-3-carbonitrile (42,25g of purity 89,5 %) was added to a solution of 14,24g (222 mmol) SO2 in 312 ml DMF in a 1000 ml teflon-coated autoclave with stirrer of PVDF. The reactor was sealed and purged for 2 min with CF3Br, followed by addition of 61,5g CF3Br. The reactor was then heated to 65°C. When the content of the autoclave had attained a temperature of 50°C, 152,6g of a 46,5% (w/w) solution of sodium formate in water was added slowly during 50 minutes while maintaining the temperature at a maximum of 68°C during the addition and at 65°C for a further 60 minute periode. During the addition of the formate-solution, the pressure increased significantly due to formation of. carbondioxide and the pressure in the reactor was reduced twice, both times followed by a limited refill (6g each time) of fresh CF3Br. The autoclave was cooled to room temperature and the pressure released through a oxidizing basic scrubber. The gas stream coining out from this scrubber was essentially free from undesired gases, containing ca. 95 % CF3Br, which was compressed and collected for reuse. The autoclave was opened and the product transferred to 750 ml water and 250 ml isopropylacetate. The phases were separated, the aquous phase extracted twice with 100 ml isopropylacetate and discarded. The combined isopropylacetate-phases were washed twice with 100 ml water and the solvent removed, resulting in 41,73 g of a crude product containg 92,9% of the product, as determined by analytical HPLC chromatography. Yield of 5- amino-3-cyano-l-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylthio- lH-pyrazole (I) was 92%. The crude product could be further purified by recrystallization from a suitable solvent or solvent-mixture, e.g. toluene or a toluene-heptane-mixture. A series of experiments using the above method is provided in Table 3. Claims 1. A process for the preparation of a compound of the formula (I) said process comprising the step of reacting in a solvent a compound of the formula (II) with a trifluoromethylhalide in the presence of a reducing system comprising a dithionite salt or a hydroxymethansulfinate salt or comprising one or more reducing agents with sulphur dioxide. 2. A process according to claim 1 wherein the reducing system comprise a dithionite salt or a hydroxymethansulfinate salt. 3. A process according to claim 2, wherein the reducing system comprise a dithionite salt, preferably sodium dithionite. 4. A process according to claim 1, wherein the reducing system comprise one or more reducing agents with sulphur dioxide. 5. A process according to claim 4 wherein the reducing agent is selected among metals, hydrazine, formic acid, salts of formate, aluminium hydrides, borohydrides and compounds of the formula (DI) wherein X represents O or S; Y1 and Y2, which may be identical or different, each represent H or O-R, where R represents a hydrogen atom, a linear or branched alkyl chain of 1-5 carbon atoms or an alkali metal atom; with the provisio that at least one of Y1 and Y2 is other than a hydrogen atom. 6. A process according to claim 5, wherein the reducing agent is an alkali metal or amine salt of formate, preferably the sodium, potassium or ammonium Sa.lt of foiixialc. 7. A process according to claim 6, wherein the reducing agent is sodium formate. 8. A process according to claim 5, wherein the reducing agent is selected among compounds of formula (HI) where X represent O, Y1 represents H or OH and Y2 represents OH or O-alkali metal 9. A process according to claim 8, wherein the reducing agent is selected among phosphorous acid (H3PO3), hypophosphorous acid (H3PO2) and sodium hypophosphorous acid (NaH2PO2). 10. A process according to claim 9, wherein the reducing agent is sodium hypophosphorous acid in one of its hydrated forms. 11. A process according to claim 1, wherein the trifluoromethylhalide is CFsBr. 12. A process according to claim 1, wherein the reaction temperature is between 20-110°C. 13. A process according to claim 12, wherein the temperature is between 30- 80°C. 14. A process according to claim 13, wherein the temperature is between 40- 60°C. 15. A process according to claim 1, wherein the solvent is dimethylformamide (DMF).

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