Method for the synthesis of 5-amino-1-phenyl-3-cyano-4-trifluoromethyl sulfinyl

Abstract

The present invention relates to a method for the preparation of the 5-amino-1-phenyl-3-cyano-4-trifluoromethyl sulfinyl pyrazole having the described general formula (I), particularly preferred for the synthesis of Fipronil I, through oxidation of a compound having the general formula (II) as follows: ##STR00001##
wherein R.sub.1 and R.sub.2 are independently hydrogen or halogen, and wherein the oxidizing agent is dichloroperacetic acid.

Claims

.[. .[.1. A method for the preparation of the compound having the following general formula (I): ##STR00008## wherein R.sub.1 and R.sub.2 are independently hydrogen or halogen; through oxidation of a compound having the general formula (II) in the presence of dichloroacetic acid and of an oxidising agent: ##STR00009## wherein R.sub.1 and R.sub.2 are defined as above, where the oxidising agent is selected from the group comprising benzoyl peroxides, sodium peroxides, t-butyl peroxides and/or hydrogen peroxide, and wherein the oxidation is conducted in the absence of trichloroacetic and/or trichloroperacetic acid..]. .].

.[. .[.2. The method according to claim 1, wherein R.sub.1 and R.sub.2 are chlorine or bromine..]. .].

.[. .[.3. The method according to claim 1, wherein the compound having the general formula (I) is 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluorometansulfinyl-1H-pyrazole-3-carbonitrile..]. .].

.[. .[.4. The method according to claim 1, wherein the dichloroacetic acid is oxidised to dichloroperacetic acid through the oxidising agent..]. .].

.[. .[.5. The method according to claim 4, wherein oxidation of the dichloroacetic acid takes place in situ..]. .].

.[. .[.6. The method according to claim 1, wherein, for each mole of compound having the general formula (I), 1.0-5.0 moles of oxidising agent are used..]. .].

.[. .[.7. The method according to claim 1, wherein, for each mole of compound having the general formula (I), 1.1-2.0 equivalents of oxidising agent are used..]. .].

.[. .[.8. The method according to claim 1, wherein, for each mole of compound having the general formula (II), 1.5 kg to 5 kg of dichloroacetic acid are used..]. .].

.[. .[.9. The method according to claim 1, wherein the temperature at which oxidation takes place is between 0° C. and 35° C..]. .].

.[. .[.10. The method according claim 1, wherein the temperature at which oxidation takes place is between 0° C.-20° C. and, preferably is 5° C..]. .].

.[. .[.11. The method according to claim 1, further comprising a step of recovering the non-oxidised compound having the general formula (II)..]. .].

.[. .[.12. The method according to claim 11, wherein the step of recovering comprises a step of dissolving and subsequently recrystallising the compound having the general formula (I) with one or more of the solvents selected from the group comprising toluene, xylene, chlorobenzene, chlorinated aliphatic solvents and isopropanol..]. .].

.[. .[.13. The method according to claim 1, wherein the oxidation of the compound having the general formula (II) occurs in the presence of an acid catalyst..]. .].

.[. .[.14. The method according to claim 13, wherein the acid catalyst is a strong mineral acid selected from the group consisting in sulphuric acid, methanesulphonic acid, hydrochloric acid, nitric acid and their mixtures..]. .].

.[. .[.15. The method according to claim 13, wherein the ratio in moles between the compound of general formula (II) and the acid catalyst is 0.3 to 1.5, and is preferably substantially equal to 0.7..]. .].

.Iadd.16. A method for the preparation of the compound having the following general formula (I): ##STR00010## wherein R.sub.1 and R.sub.2 are independently hydrogen or halogen; through oxidation of a compound having the general formula (II) in a reaction mixture of dichloroacetic acid and hydrogen peroxide: ##STR00011## wherein R.sub.1 and R.sub.2 are defined as above, and wherein the oxidation is conducted in the absence of trichloroacetic and trichloroperacetic acid, and wherein dichloroacetic acid is oxidized to dichloroperacetic acid in situ through the hydrogen peroxide, and dichloroperacetic acid oxidizes the compound of general formula (II) to the compound of general formula (I). .Iaddend.

.Iadd.17. The method according to claim 16, wherein R.sub.1 and R.sub.2 are chlorine or bromine. .Iaddend.

.Iadd.18. The method according to claim 16, wherein the compound having the general formula (I) is 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)pyrazole-3-carbonitrile. .Iaddend.

.Iadd.19. The method according to claim 16, wherein the temperature at which oxidation takes place is between 0° C. and 35° C. .Iaddend.

.Iadd.20. The method according to claim 16, wherein the temperature at which oxidation takes place is between 0° C. and 20° C. .Iaddend.

.Iadd.21. The method according to claim 16, wherein the temperature at which the oxidation takes place is about 5° C. .Iaddend.

.Iadd.22. The method according to claim 16, wherein, for each mole of compound having the general formula (I), 1.0-5.0 moles of hydrogen peroxide are used. .Iaddend.

.Iadd.23. The method according to claim 16, wherein, for each mole of compound having the general formula (I), 1.1-2.0 equivalents of hydrogen peroxide are used. .Iaddend.

.Iadd.24. The method according to claim 16, wherein, for each mole of compound having the general formula (II), 1.5-5 kg of dichloroacetic acid are used. .Iaddend.

.Iadd.25. The method according to claim 16, wherein, the oxidation is conducted at a temperature between 0° C. and 20° C., for each mole of compound having the general formula (I), 1.0-5.0 moles of hydrogen peroxide and 1.5-5 kg of dichloroacetic acid are used. .Iaddend.

.Iadd.26. The method according to claim 16, wherein, 80%-98% of the compound having the general formula (II) is converted to the compound having the general formula (I). .Iaddend.

Description

EXAMPLE 1

Synthesis of Fipronil

(1) In a glass reactor, 421 grams (1.0 moles) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluorometan-sulfanil-1H-1-pyrazole-3-carbonitrile hereafter “sulphide”) are dissolved in 2300 grams of dichloroacetic acid (DCA). The solution obtained is stirred and kept at 20° C. after which 102 grams of hydrogen peroxide in an aqueous solution 50% w/w (1.5 moles) are added.

(2) The reaction is monitored using HPLC analysis until it reaches a conversion level of more than 95% of the reagent sulphide, after which the reaction mixture is diluted with 4 liters of water until the product has precipitated entirely.

(3) The solid thus obtained is filtered, washed with water and dried to obtain 420 grams of product with a purity of 93.5%.

EXAMPLE 2

Synthesis of Fipronil with Subsequent Recovery of Unconverted Reagent Compound Having the General Formula (II)

(4) In a glass reactor 421 grams (1.0 mole) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluorometan-sulfanil-1H-pyrazole-3-carbonitrile (hereafter “sulphide”) are dissolved in 2300 grams of dichloroacetic acid (DCA). The solution obtained is stirred and kept at 20° C., after which 102 grams of hydrogen peroxide in an aqueous solution 50% w/w (1.5 moles) are added.

(5) The reaction is monitored using HPLC analysis until it reaches a conversion level of 92% of the reagent sulphide, so as to limit the formation of the by-product (III) difficult to remove by means of re-crystallisation. When the desired conversion level has been reached the reaction mixture is diluted with 4 liters of water until the product has precipitated entirely.

(6) The solid thus obtained is filtered, washed with water and dried.

(7) After drying the raw product is dissolved while hot in chlorobenzene solvent and re-crystallised by cooling to a low temperature. The solid thus obtained is composed of Fipronil with a purity of over 95%.

(8) The filtrate, containing only sulphide and small quantities of Fipronil, is deprived of the solvent chlorobenzene and added as a reagent to a subsequent oxidation reaction.

EXAMPLE 3

Synthesis of Fipronil with Addition of Sulphuric Acid and Comparison With Example 1 and with WO 2007/122440 A1

(9) In a glass reactor 421 grams (1.0 mole) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluorometan-sulfanil-1H-pyrazole-3-carbonitrile (hereafter “sulphide”) are dissolved in 2300 grams of dichloroacetic acid (DCA). The solution obtained is stirred and kept at 20° C. and subsequently 102 grams of hydrogen peroxide in aqueous solution 50% w/w (1.5 moles) and 70 grams (0.7 moles) of H.sub.2SO.sub.4 are added.

(10) The reaction is conducted at a temperature of 5 to 10° C. and monitored by means of HPLC analysis until it reaches a conversion level of over 95% of the reagent sulphide, after which the reaction mixture is diluted with 4 liters of water until the product has precipitated entirely.

(11) The solid thus obtained is filtered, washed with water and dried to obtain 420 grams of a product with a titre of 93.5%.

(12) According to this example, the desired conversion level is reached in about 3 hours compared to the 20 hours of the previous example 1. The reaction conducted at 20° C. according to the examples shown in the earlier document WO 2007/122440 A1, mentioned at the beginning, lasts about 8 hours.

(13) Innovatively, the method of the present invention is conducted in the presence of an oxidising agent and of dichloroacetic acid making a plurality of operations superfluous, for example dissolution, otherwise essential in the known methods.

(14) Advantageously, the method of the present invention allows to achieve higher yields compared to the methods of the prior art, in that the reaction takes place with improved selectivity thereby preventing the consumption of useful product in parasite reactions.

(15) Advantageously, the method of the present invention, once the excess of unconverted reagent (II) has been easily recovered, makes subsequent purification of the compound having the general formula (I) superfluous, which as well as being burdensome in itself is economically disadvantageous.

(16) Advantageously, the use of the oxidising agent of the present invention does not require the use of solvents for the reaction, making the entire process much simpler and economically advantageous in industrial applications.

(17) In fact, according to a further advantageous aspect, the cost of such oxidant is lower than the cost of the oxidants traditionally used.

(18) Advantageously, the function performed by the DCA in the method of the present invention enables economies in terms of costs of the reagents, and simplification of the plant for implementing the teaching.

(19) Advantageously, the process of the present invention makes the use of corrosion inhibitors superfluous and allows to drastically increase the useful life of the equipment used.

(20) It was, in fact, observation of the premature corrosion of the plants which urged the authors of the present invention to look for an oxidant agent alternative to the oxidants traditionally used.

(21) As a result, the aforesaid advantage is twofold in that it derives both from the non-use of a corrosion inhibitor and from the increased useful life of the equipment.

(22) Advantageously, the addition of an acid catalyst makes it possible to considerably reduce reaction times while maintaining a high degree of selectivity of oxidation of the compound having the general formula (II).

(23) Even if not previously specified, a person skilled in the art may, using the expertise typical of the sector, vary or replace some of the aspects described above with other technically equivalent ones.

(24) For example, dichloroperacetic acid may be prepared separately from the place where oxidation of the compound having the general formula (II) takes place, for subsequent addition to the latter.

(25) Moreover, one embodiment envisages that the peroxides illustrated earlier may be replaced or used in conjunction with a peracid and/or a persulphate.

(26) These variations or replacements also fall within the scope of protection defined by the following claims.

(27) In addition, any alternative shown in relation to a particular embodiment may be realised independently of the other variations described.