FI114153B - New N-phenyl:pyrazole cpds. and intermediates - useful for control of arthropod, plant nematode, helminth or protozoan pests - Google Patents

Abstract

N-phenylpyrazole derivs. of formula (I) are new: where R1 = CN, NO2, halo, Ac or CHO; R2 = R5SO2, R5SO or R5S; (R5 = opt. branched alkyl, alkenyl or alkynyl of up to 4C, opt. substd. by opt. different halogen(s)); R3 = H, halo, -NR6R7, opt. branched alkoxymethyleneamino contg. 2-5C and opt. substd. on the CH2 by an opt. branched 1-4C alkyl gp. or opt. branched 2-5C alkoxycarbonyl opt. substd. by halogen(s); (R6, R7 = H, opt. branched alkyl, alkenylalkyl, or alkynylalkyl of up to 5C, CHO or 2-5C opt. branched alkanoyl or haloalkanoyl; or NR6R7 = 5-or 6-membered cyclic imide); R4 = phenyl substd. in the 2-posn. by F, Cl, Br or I; in the 4-posn. by opt. branched 1-4C alkyl or alkoxy (opt. substd. by halogen(s)) or a Cl or Br; and opt. in the 6-posn. by F, Cl, Br or I; with the exclusion of the cpd. where R1 = Cn, R2 = MeSO2, R3 = NH2 and R4 = 2,6-dichloro-4-tri fluoromethylphenyl. Pref. in (I): (i) R1 is not CHO and neither R6 or R7 is alkenylalkyl or alkynylalkyl; (ii) R2 = 1-4C alkylsulphonyl/sulphinyl/thio opt. halogen substd. or up to 4C alkenyl- or alkynyl-sulphonyl/sulphinyl/thio opt. halogen substd.; R3 = H, NH2, or NHMe; and R1 = halogen, or esp. CN or NO2; and esp. (iii) R4 contains a CF3 or OCF3 gp.; and R2 = opt. halogenated 1-4C alkylsulphionyl/sulphinyl/thio gp.; partic. R2 = SCF3, SOCF3, or SO2CF3; and R4 = 2,4,6-trichloro-, or 2,6-dichloro-4-difluoromethoxy-, 2-chloro-4-trifluoromethyl-,etc.

Description

114153

Process for the preparation of a therapeutically active N-phenylpyrazole derivative Partitioned from application 882735.

The invention relates to a process for the preparation of a therapeutically active N-phenylpyrazole derivative.

EP-A-201852 discloses insecticides, mites and nematodes as 1-aryl-5-aminopyrazoles wherein the 3-position is unsubstituted or substituted by an alkyl or haloalkyl group and the 4-position is substituted by alkyl, aralkyl or arylsulfenyl. a sulfinyl or sulfonyl group.

EP-A-245875 discloses 1-aryl-4-cyano-5-15 aminopyrazoles as acaricides having an alkylsulfenyl, sulfinyl or sulfonyl group at the 3-position.

FI Patent Application 865195, to which PL 2 § 2 applies, discloses a method for controlling arthropods, plant nematodes or protozoa using compounds of the general formula S

: Y: H

LH

J · -ji- (R) "

..,: where Y represents a halogen or a cyano, nitro, RSO2, RSO or RS group in which R

25 is an alkyl, cycloalkyl or alkenyl, thiocyanato, sulfamoyl, carbamoyl, alkoxycarbonyl, alkanoyl or alkyl group; Z represents a hydrogen atom, an amino group -NR 1 R 2, an alkylsulfenylamino, an alkoxymethylenylamino, a halogen, a: alkyl, carboxyl, alkylthio, alkylsulfinyl or alkylsulfonyl, trialkylsilylmethyl, trialkylsilyl, cyano or a nitro group; R 4 represents a halogen 30 atom, alkyl, alkoxy, halo-substituted alkylthio or alkylsulfinyl,? 2 nitro, cyano or alkylsulfonyl groups; R 4 represents a halogen atom, a cyano, nitro, alkyl or cycloalkyl group and N represents an integer from 1 to 5, or salts thereof, provided that R 1, Y and Z do not simultaneously represent a nitro, cyano, halogen or unsubstituted alkyl group .

5

The invention provides N-phenylpyrazole derivatives of the general formula (I) as shown below, wherein R 4 is a cyano or nitro group or a halogen atom, R 4 is a group R 6 SO or R 6 S wherein R 6 is straight or a branched alkyl, alkenyl or alkynyl group (preferably 1- (alkynyl) alkyl or even more preferably alk-2-ynyl) having up to 4 carbon atoms and which may be unsubstituted or substituted by one or more halogen atoms may be the same or different, R 4 is a hydrogen atom or an amino or methylamino group, a 2,6-dichloro-4-trifluoromethyl or a 2,6-dichloro-4-trifluoromethoxyphenyl group. These compounds have valuable activity against arthropods, parasitic worms and protozoa in therapeutic use.

Most preferred compounds of the general formula (I) are those wherein R 1 is an alkyl, alkenyl or alkynyl sulfonyl or thio group which is optionally halogen substituted and contains 1 to 4 carbon atoms, preferably a trifluoromethylthio or tri-fluoromethylsulfonyl group, R1 is a hydrogen atom, an amino or methylamino group, and R1 is a halogen atom or preferably a cyano or nitro group.

• »♦: ·. · Compounds of general formula (I) of great interest, *. ! are as follows: 1. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethyl:: thiopyrazole.

v: 2. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethoxyphenyl) -4-trifluoromethylthiopyrazole.

3. 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-difluoromethyl- "': thiopyrazole.

1. 4. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-heptafluoropropylthiopyrazole.

; 5'-5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trichloromethyl-; 35 thiopyrazole.

; 6. 5-Amino-3-chloro-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole.

11415.7.37-5-amino-3-bromo-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethyl-thiopyrazole.

8. 5-Amino-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -3-fluoro-4-trifluoromethyl-thiopyrazole.

9. 9. 5-Amino-4-chloro-difluoromethyl-thio-3-cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -pyrazole.

10. 3-Cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -5-dimethylamino-4-trifluoromethyl-thiopyrazole.

11. 3-Cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-thiopyrazole.

12. 3-Cyano-1- (2,6-dichloro-4-trifluoromethoxyphenyl) -4-trifluoromethylthiopyrazole.

13. 1- (2,6-Dichloro-4-trifluoromethyl-phenyl) -3-iodo-4-trifluoromethyl-thiopyrazole.

14. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethyl-sulfmylpyrazole.

15. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethoxyphenyl) -4-trifluoromethylsulfmylpyrazole.

16. 3-Cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylsulfonylpyrazole.

17. 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4- (1-methylprop-2-ynylsulfinyl) pyrazole.

. :. 18. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-methylsulfinyl. lipyratsoli.

; 19. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-isopropylsul-1 '25 -phenylpyrazole.

20. 5-Amino-3-bromo-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethyl: sulfinylpyrazole.

21. 1- (2,6-Dichloro-4-trifluoromethyl-phenyl-3-nitro-4-trifluoromethylsulfinyl-pyrazole.

22; 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-methylthiopyrazole: ''; Soli.

'. 23. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-ethylthiopyrazole.

; '24. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-propyl-thiopy-?

'; 25. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-isopropylthiopyrazole.

11415.7 4 26. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4- (2-methylpropylthio) pyrazole.

27. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4- (1-methylpropylthio) pyrazole.

28. 28. 4-Allylthio-5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole.

29. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4- (prop-2-ynylthio) pyrazole.

30. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4- (1-methyl-10-prop-2-ynylthio) pyrazole.

31. 5-Amino-3-bromo-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-methyl-thiopyrazole.

32. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-tert-butylthio-pyrazole.

15 3 3.5-amino-3-bromo-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-methylsulfinylpyrazole.

34. 3-Cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -5-methyl-amino-4-trifluoromethyl-thiopyrazole.

5,5-amino-3-cyano-4-dichlorofluoromethylthio-1- (2,6-dichloro-4-trifluoromethyl-phenyl) pyrazole.

36. 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-pentafluoroethylthiopyrazole.

.. 37. 3-Cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -5-dimethylamino-4-trifluoro *. ! rimetyylisulfinyylipyratsoli.

38. 5-Amino-4- (2-chloro-1,1,2-trifluoroethylthio) -3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole.

: Numbers 1-38 are assigned to the above compounds for subsequent identification and labeling.

- 30

The invention makes it possible to control arthropods, parasitic worms and protozoa '. therapeutic use comprising treating or administering an effective amount of a compound of general formula (I).

::: 35 The compounds of general formula (I) may be used in particular in veterinary medicine

* I I

;. for the control of arthropods, parasitic worms and protozoa that are internal or external to parasites in vertebrates, especially warm-blooded vertebrates, e.g., humans and domestic animals such as cattle, sheep, in fish, e.g. Acarina, comprising mites (e.g., Ixodes sp., Boophilus sp., e.g. Boophilus microplus, Amblyomma sp., Hyalomma sp., Rhipicephalus sp., e.g. Rhipicephalus appendiculatus, Haemaphysalis sp., Dermacentor sp. Omithodorus sp. (E.g. Omithodorus moubata) and mites (e.g. Damalinia sp., Dermahyssus gallinae, Sarcoptes sp. E.g. Sarcoptes scabiei, Psoroptes sp., Chorioptes sp., Demodex sp., Eutrombicula sp.), Diptera (e.g. Aedes sp., Anopheles sp., Musca sp., Hypoderma sp., Gasterophilus sp., Simulium sp.), Hemiptera (e.g. Triatoma sp.), Phthiraptera (e.g. Damalinia sp., Linognathus 10 sp.), Siphonapter. a (e.g. Ctenocephalides sp.), Dictyoptera (e.g. Periplaneta sp.,

Blatella sp.); and Hymenolepis Nana worms in the control and treatment of diseases caused by protozoa such as Eimeria sp., e.g., Eimeria tenella, Eimeria acervulina, Eimeria brunetti, Eimeria maxima and Eimeria necatrix, Trypanosoma cruzi, Leishmania sp., Plasmodium sp. , Trichomonadidae sp., Histomonas sp., Giardia sp., Toxoplasma sp., Entamoeba histolytica and 20 Theileria sp.

, *; · To reduce the number of arthropods and nematodes, the active compound is added. . usually to the point where the growth of arthropods and nematodes must be contained.

; Under ideal conditions, depending on the pest being treated, even a smaller amount of ** '·' 25 may be sufficient to provide protection. On the other hand, in severe climatic conditions, pest resistance and other factors may require greater use of the active agent i.i.

•

The compounds of general formula (I) are of great value in responding to; · · 30 arthropods, parasitic worms and protozoa, which are harmful to humans and domestic animals, such as those mentioned above, or transmit or carry diseases, and especially to kill mites, lice, fleas, mosquitoes. and biting, annoying and] 'myotic flies. The compounds of general formula (I) are very useful in the treatment of arthropods, parasitic worms and protozoa which are present in: or in, or on the skin or skin of, domestic animals, for which these compounds may be administered orally, parenterally, percutaneously or superficially.

114153 6

Coccidiosis disease, caused by protozoa of the genus Eimeria, is an important cause of economic losses in livestock and birds, especially those reared or kept under efficient conditions. For example, cattle, sheep, pigs and rabbits can become ill, but this disease is very important in poultry, especially chickens.

Poultry diseases are transmitted by common birds, which kill infectious organisms on the substrate or in the faeces of the ground, or through feed or drinking water. Symptoms of this disorder are bleeding, accumulation of blood 10 in the avian caecum, faecal blood, weakness and indigestion. The disease often results in the death of the animal, but in live birds the infection causes a significant reduction in their marketing value.

Administration of a small amount of a compound of general formula (I), preferably in combination with poultry feed, effectively prevents or greatly reduces the occurrence of coccidiosis. These compounds are effective against both the caecal form (caused by E. tenella) and the intestinal forms (caused mainly by E. acervulina, E.brunetti, E. maxima and E. necatrix).

20

Suitable ways of using the compounds of general formula (I) are, for example, the following:! for parenteral, oral or topical administration of compositions in which the active ingredient has immediate and / or long-lasting activity against arthropods, parasites or protozoa, to persons or animals exposed to or susceptible to diseases caused by arthropods, parasitic worms or protozoa. · · For example, by combining them with food or suitable oral pharmaceutical products, baits, lime stones, nutritional additives, * * 30 supplements, sprays, baths, showers, dusting products, fats, ''; shampoos, creams, waxes and livestock treatment systems, generally '. to the environment or to specific areas in which pests may occur, in the form of showers, mists, powders, smoke, waxes, varnishes, granules and bait; 'Running water and standing water, or livestock feed in their stools; ; 35 to kill flies.

»

The compounds of general formula (I) may be added to destroy arthropods, parasitic worms and protozoa in any type of mixture suitable for use in 11415; For administration to vertebrates, either internally or externally, containing as active ingredient at least one compound of general formula (1) in combination with one or more suitable diluents or additives suitable for their intended use. Such mixtures may be prepared in any known manner.

Formulations suitable for administration to vertebrates or humans include, for example, those suitable for oral, parenteral, percutaneous or topical administration.

10

Formulations for oral administration contain one or more compounds of general formula (I) in association with pharmaceutically acceptable carriers or coatings and include, for example, tablets, pills, capsules, tackles, gels, medicated drinks, nutritional supplements, and water supplements, slow-release capsules or other slow-release products designed to stay in the digestive tract. All of these may be supplemented with the active ingredient in microcapsules or coated with acid or alkali labile or other pharmaceutically acceptable enteric coatings. Mixed feeds and concentrates containing the compounds of the invention may also be used in the preparation of a drug-containing nutrient, drinking water, or other animal product.

Mixtures suitable for parenteral administration include, for example, solutions, emulsions and I · ',; suspensions in any suitable pharmaceutically acceptable medium, '' '' and solid or semi-solid subcutaneous preparations or spheres, intended to release the active ingredient over a prolonged period of time, which may be:.:: prepared and sterilized by any suitable route. in a known way.

Formulations suitable for percutaneous and topical administration include sprays, dusts, baths, showers, creams, shampoos, fats, waxes, or finished products and devices (eg, ear tags) that are externally applied to the animal to provide *, local or systemic arthropod adjustment.

t * 'I

· Solid and liquid baits suitable for controlling the number of arthropods: 35 comprise one or more compounds of general formula (I) and a carrier or diluent which may contain a food or other substance, which the arthropod eats.

114153 8

Liquid mixtures include water-miscible concentrates, emulsifiable concentrates, flexible suspensions, wetting or solubilizing agents containing one or more compounds of general formula (I) that can be used to treat substrates or sites where arthropods are present or may occur.

Mixtures in the form of aerosols and solutions or dispersions, whether or not containing water, suitable for spraying, spraying or spraying in very small volumes of 10 volumes may also be used.

Solid diluents which may be used in the preparation of compositions suitable for incorporation of the compounds of general formula (I) include, for example, aluminum silicate, diatomaceous earth, maize residues, tricalcium phosphate, powdered cork, absorbent carbon, magnesium silicate, clay such as kaolin. or attapulgite, and water-soluble polymers, and such solid mixtures may, if desired, contain one or more suitable wetting, dispersing, emulsifying or coloring agents which, if solid, may also serve as diluents.

Such solid compositions, which may be in the form of dusts, granules or wettable powders, are generally prepared by impregnating solid diluents with solutions of the compound of general formula (I) in volatile solvents, evaporating these solvents and, if necessary, milling the products to obtain a powder. , and, if desired, granulating or compressing these products to obtain granules, spheres or extrudates, or encapsulating the finely divided active ingredient in natural or synthetic polymers, e.g., gelatin, synthetic resins: quinol polyamides.

• f I

• · ·

The wetting, dispersing and emulsifying agents which may be used in particular in the wettable powders may be of the ionic or non-ionic type, e.g. sulforicin oleateates, quaternary ammonium derivatives, or products based on ethylene oxide condensates, with carboxylic acid esters of nonyl and octyl phenols or anhydrosorbitols, which are made soluble by etherification of free hydroxy groups by condensation with ethylene oxide; 35, or mixtures of these types of substances. Wettable powders may be treated with water immediately prior to use to prepare ready-to-use suspensions.

114153 9

Liquid mixtures for incorporation of compounds of general formula (I) may be in the form of solutions, suspensions or emulsions of compounds of general formula (I), optionally encapsulated in natural or synthetic polymers, and may optionally contain wetting, dispersing or emulsifying agents. Such emulsions, suspensions and solutions may be prepared using aqueous organic or organic diluents, e.g., acetophenone, isophorone, toluene, xylene, mineral, animal or vegetable oils, and water-soluble polymers (and mixtures of these diluents), whether or not ionic. ionic wetting, dispersing and emulsifying agents, or mixtures thereof, e.g. If desired, emulsions containing the compounds of general formula (I) can be used in the form of self-emulsifiable concentrates containing the active ingredient dissolved in emulsifiers or emulsifier-containing solvents compatible with the active ingredient, thereby simply adding water to these concentrates to form ready-to-use mixtures. 15

Mixtures containing compounds of general formula (I) and which may be used to destroy arthropods, parasitic worms and protozoa may also contain synergistic agents (e.g., piperonyl butoxide or sesamex product), stabilizers, other insecticides, antiparasitic agents or anticocci, fungicides (used in veterinary medicine, eg benomyl and iprodione), bactericides, arthropods or invertebrates, or. : ·. repellents, or pheromones, rhododorants, flavors, dyes, and additional therapeutic agents, e.g., trace elements. They can be used to improve efficiency, »· \! endurance, security, and broadening the spectrum of pests to be controlled, or to allow these compositions to produce other beneficial effects in the same treated animal or region.

* .: · Examples of other insecticides which may be used in this connection with the compounds of the invention are: acephate, chlor-; * 30 pyrifos, demeton-S-methyl, disulfoton, ethoprophos, fenitrothion, malathion, monocrotophos, parathion, phosalone, primiphosmethyl, triazophos, cyfluthrin, cy- '. permethrin, deltamethrin, fenpropathrin, fenvalerate, permethrin, aldicarb, carbosulfan, methomyl, oxamyl, pirimicarb, bendiocarb, teflubenzuron, dicofol, endosulfan, lindane, benzoximate, cartap, cyhexatin, tetradifon, avermectin: , thiophanate, trichlorfon, dichlorvos, diaveridine and dimetridazole.

Mixtures used for the control of arthropod, parasitic or protozoan pests generally contain from 0.00001% to 95%, more particularly 11415310 0.0005-50% by weight, of one or more compounds of general formula (I) or active ingredients as a whole (i.e., a compound of general formula (I) or compounds thereof in combination with other compounds which are toxic to arthropods, and parasitic and coccidial pesticides, synergists, trace elements or stabilizers). The mixtures to be used and the amount to be added shall be chosen so as to obtain the desired effect by the animal breeder, pest control operator or other person skilled in the art. Such solid and liquid mixtures, when added to the surface or stored products, usually contain from 0.00005 to 90%, in particular 0.001 to 10% by weight, of one or more compounds of general formula (I). When administered orally or parenterally or percutaneously to animals, solid or liquid compositions generally contain from 0.1 to 90% by weight of one or more compounds of general formula (1). Medicated feeds usually contain from 0.001 to 3% by weight of one or more compounds of general formula (I). The concentrates and additives which are incorporated into the feed usually contain from 5 to 90% and preferably from 5 to 50% by weight of one or more compounds of general formula (I). Mineral flagstones usually contain from 0.1 to 10% by weight of one or more compounds of general formula (I).

Powders and liquid mixtures for administration to livestock or humans may contain 0.0001-15%, preferably 0.005-2.0% by weight, of one or more of the general formula (I): ·. . A suitable concentration in the treated waters is between 0.0001 ppm and

t I

A, 20 ppm, and preferably 0.001 to 5.0 ppm, one or more compounds of general formula (I), and may also be used therapeutically in fish farming with an appropriate withdrawal period. The baits may contain from 0.01% to 5%, and preferably from 0.01% to 1.0% by weight, of one or more compounds of general formula (I).

v: When administered to vertebrates parenterally, orally or percutaneously or otherwise, the dosage of the compounds of general formula (I) will depend upon this; · 30 vertebrate species, age and health, and their nature or degree: actual or potential contamination by arthropod, parasitic or protozoan pests. A single dose of 0.1 to 100 mg, preferably 2.0 to 20.0 mg, per kg body weight of the animal, or doses of 0.01 to 20.0 mg, preferably 0.1 to 5.0 mg, per kg body weight of the animal at 35 days for long-term medication are generally suitable for oral or parenteral administration. When using slow release formulations or products, the daily doses required over a period of months can be administered to the animals at once.

114153 11

Activity tests against arthropods carried out using representative compounds of the invention gave the following results (where ppm is the concentration of the compound in one millionth of the test solution used).

5 Experiment 1

One or more dilutions of the compounds to be tested were performed in 50% aqueous acetone.

10 (a) Test species: Plutella xylostella (cabbage) and Phaedon cochleariae (mustard bark).

Pieces of the turnip leaf were added to the agar in petri dishes and infected with 10 larvae (step 2 with Plutella or step 3 with Phaedon). In each experiment, four identical-15 plates were used and sprayed with the corresponding test solutions under the Potter Tower. Four or five days after treatment, the plates were removed from the constant temperature room (25 ° C) where they were kept and the average larval mortality rate was determined. These values were compared with the mortality in the plates treated with 50% aqueous acetone alone, which was used as a reference.

: ·. (b) Megoura viciae (ax)

Bean plants in pots that were pre-infected with Megoura Phase Mixture. ! , was sprayed down to the run using a mobile laboratory spray device ** **. Treated plants were kept in a greenhouse for 2 days and aphid mortality was determined using a system that judged the result compared to plants treated with 50% aqueous acetone alone. Each treatment was repeated four times.

; · 30 Grade 3 all aphids dead: '': 2 few aphids alive '. 1 most aphids alive' _ / 0 non-essential mortality: 35 (c) Test species: Spodoptera littoralis; French bean leaf parts were added to agar in petri dishes and infected with 5 larvae (step 2) Four dishes were used for each treatment and a corresponding test solution was sprayed underneath the Potter Tower, and after 2 days, transplant 11415/12 into rare live larvae containing similar leaves containing untreated leaves on agar 2 or 3 days later from a room kept at a constant temperature (25 ° C), and the average larval mortality rate was determined and compared to mortality in plates treated with 50% aqueous acetone alone for comparison.

Following the above procedure, the following compounds were added to kill Plutella xylostella larvae, resulting in at least 65% mortality of less than 500 ppm: 1-4, 6-18, 20-23, 29-32, 34-36.

According to the above method, the addition of the following compounds was effective against all steps of Megoura viciae to give a value of 7/12 at 50 ppm: 5, 19, 24, 25, 26, 27, 28.

15

According to the above method, the addition of the following compounds was effective against Phaedon cochleariae larvae, resulting in at least 90% mortality below 5 ppm: 33.

20 The following conjunction symbols describe mixtures which may be used for pests of arthropods, nematodes, parasitic worms or protozoa:. containing compounds of the general formula (I) as active ingredient. The mixtures described in conjunction with Examples 1-6 may each be diluted with water. ! so as to obtain sprayable compositions at concentrations suitable for this purpose.

'·'> Alloy Example 1

The aqueous concentrate was prepared from γ-5-amino-3-cyano- (2,6-dichloro-4-trifluoromethylphenyl) -4-; ": Trifluoromethylthiopyrazole 7% w / v, Ethylan BCP 10% w / v, and N-methylpyrrolidone to 100% v / v by dissolving Ethylan BCP in a portion of N-methylpyrrolidone and then adding: the ingredient while heating and stirring until dissolved. Solution obtained:: brought to the desired volume by addition of the remainder of the solvent.

Mixture Example 2 13 114153

The emulsifiable concentrate was prepared from 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-5 trifluoromethylthiopyrazole 7% w / v

Soprophor BSU 4% w / v

Arylan CA 4% w / v N-methylpyrrolidone 50% w / v and Solvesso 150 100% v / v by dissolving Soprophor BSU, Arylan CA and the active ingredient in N-methylpyrrolidone and then adding Solvesso 150 to the desired volume.

Mixture Example 3 A wettable powder was prepared from the following ingredients: 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole 40% w / w

Arylan S 2% w / w

Darva No. 2 up to 5% w / w 20 and Celite PF 100% w / w by mixing the ingredients and grinding the mixture in a hammer mill to a fraction of the size. : ·. I make less than 50 microns.

• * ·! Alloy Example 4 * · '·; 25

An aqueous fluid mixture was prepared from the following ingredients: 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4- v · trifluoromethylthiopyrazole 30% w / v

Ethylan BCP 1% w / v ·: 30 SoproponT36 0.2% w / v: ethylene glycol 5% w / v. Rhodigel23 0.15% w / v and water 100% by volume; 'By thoroughly mixing the ingredients and grinding in a ball mill therefore: · 35 until the average particle size is less than 3 microns.

Alloy Example 5 114152 14

The emulsifiable suspension concentrate was prepared from the following ingredients: 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-5 trifluoromethylthiopyrazole 30% w / v

Ethylan BCP 10% w / v

Bentone 38 0.5% w / v and Solvesso 150 100% by volume by thorough mixing and grinding in a ball mill until the average particle size was less than 3 microns.

Alloy Example 6

Water dispersible granules were prepared from the following ingredients: 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole 30% w / w

Darwin n 2 2 15% w / w

Arylan S 8% w / w and Celite PF up to 100% w / w by mixing the ingredients, grinding in a liquid energy mill and then granulating in a rotary spheronizer by spraying with sufficient water (always 10% w / w). The resulting granules were dried in a fluid bed dryer to remove excess water.

25 Descriptions of commercial products used in the above related brands: Ethylan BCP Nonyl Phenol Ethylene Oxide Condensate: SoprophorBSU Tristyryl Phenol and Ethylene Oxide Condensate: Arylan CA 70% w / v solution of calcium dodecyl benzene sulfonate

Solvesso 150 light C 10 aromatic solvent; * 30 Arylan S sodium dodecylbenzene sulfonate ': Darva sodium lignosulfonate'. Celite PF Synthetic Magnesium Silicate Carrier Sopropone T36 Polycarboxylic Acid Sodium *; 'Rhodigel 23 polysaccharide xanthan gum:: 35 Bentone 38 Organic derivative of magnesium montmorillonite

Mixture Example 7 15,114,153 A dusty powder can be prepared by intimately mixing the following ingredients: 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole 1-10% w / w wt / wt) very fine talc up to 100% by weight This powder may be added to arthropods, such as remote sites or landfills, stored products, household products or animals that are infected or at risk of being infected with arthropods. to destroy the oral route. Suitable ways to add dusting powder to arthropod sites include the addition of mechanical blowers, hand shovels, and automated livestock handling equipment.

15

Alloy Example 8

The bait can be prepared by thoroughly mixing the following ingredients: 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole 0.1-1.0% w / w. ; · Wheat flour 80% w / w; · \ Molasses to 100% w / w 25 This bait can be added to a suitable location, e.g. residential and industrial buildings such as kitchens, hospitals or warehouses, or areas where arthropods such as ants, locusts, cockroaches and flies are present , to destroy arthropods by oral route.

Compound Example 9 'A solution may be prepared containing: 5% w / v 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethyl-methyl-phenyl) -4-trifluoromethyl-thiopyrazole : 35 dimethylsulfoxide in 100% volume by dissolving the pyrazole derivative in a portion of dimethylsulfoxide and then adding more dimethylsulfoxide to the desired volume. This solution can be added to domestic arthropods by percutaneous drainage of 11415316 or after sterilization by filtration through a polytetrafluoroethylene film (pore size 0.22 µm) using parenteral injection in an amount of 1.2 to 12 ml solution per 100 kg body weight of the animal.

5 Alloy Example 10

The wettable powder can be prepared from the following ingredients: 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole 50% w / w 10 Ethylan BCP (nonylphenol-ethylene oxide condensate containing 9 moles ethylene oxide per mole of phenol) 5% w / w

Aerosil (fine particle size silica) 5% w / w

Celite PF (synthetic magnesium silicate carrier) 40% w / w by adsorbing Ethylan BCP Aerosil, mixing with other ingredients and grinding the mixture in a hammer mill to obtain a wettable powder which can be diluted with water to a concentration of 0.001 to 2% w / v pyrazole compound. larvae or plant nematodes, by spraying or livestock showing or likely to have arthropods, parasites or protozoa, by spraying or dipping or administering orally to drinking water to destroy arthropods, parasites and protozoa.

. Alloy Example 11 I i <\! Slow release tablets may be made from granules containing a thickening tablet. 25 agents, binder, sustained release agent, and 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole compound at various percentages by volume. By compressing such a mixture, a tablet of οπήν: female weight of 2 or greater may be prepared and such tablets may be administered to orally ruminant domestic animals to provide a suppressive effect on the reticulum by sustained release of the pyrazole compound over a prolonged period of time in arthropods to counter it. rotting domestic animals.

Alloy Example 12 35; The sustained release mixture can be prepared from the following ingredients: 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole 0.5-25% w / w polyvinyl chloride base 100% p / p by mixing 114,152,17 polyvinyl chloride base with a pyrazole compound and a suitable plasticizer, e.g. dioctyl phthalate, and extruding the homogenous mixture obtained by melt or casting into a suitable form e.g., granules, spheres, extrudates or strips, which may be added e.g. in the case of 5, by forming a neckband or ear tag for attachment to a domestic animal for killing insects upon slow release of the pyrazole compound.

Similar mixtures can be prepared by substituting the corresponding amount of another compound of general formula (I) for 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole in these linker moieties.

Compounds of general formula (I) may be prepared using or applying known methods (i.e., methods previously used or described in the chemical literature), wherein the formation of the pyrazole ring is usually followed if necessary by exchange of substituents.

It will be appreciated that the following procedures may be used to describe the order of attachment of the various groups to the pyrazole ring and that suitable protecting groups may be required, as will be apparent to one skilled in the art: the compounds of general formula (I) may be converted to other compounds of general formula .

In the following explanation, if there are no specific symbols in the formulas! as defined herein, it is to be understood that they are "as hereinbefore defined" according to the first definition of each sym- '' '' '' '' s in this specification. Described herein is an amino, unless otherwise stated, an unsubstituted amino group.

»* · •. Compounds of general formula (I) wherein R 1 is R 6 SO or R 5 S, R 6 is an unsubstituted amino group and R 1 is a cyano group can be prepared by method -; * with modification (a) wherein The compound of formula (II) wherein R 4 is: a cyano group is reacted with a compound of the general type '. R 4 -C 6 CN, preferably using an equivalent molar amount, usually in the presence of an anhydrous inert organic solvent, e.g. ethanol, and an equivalent molar amount of a base, e.g. sodium ethoxide, at a temperature of 0 ° C to 50 ° C.

: 35; Compounds of general formula (I) wherein R 4 is a R 6 group and R 4 is an amino or methyl amino group can be prepared by process variant (b) 11415.718, wherein the intermediate of general formula (I) wherein R 2 is replaced by a hydrogen atom is reacted with a compound of the general formula: R 5 -SC 1 (III) 5 (wherein R 1 is as defined above) in an inert organic solvent, preferably chloroform or dichloromethane, optionally a base, preferably pyridine , in the presence of 0 to 50 ° C.

Compounds of general formula (I) wherein R 1 is a chlorine or fluorine atom, R 2 is a R 1 SO or R 1 S group and R 2 is an amino group can be prepared according to a variant of process (c) wherein wherein X and Y are both chlorine or fluorine, is reacted with a phenyl hydrazine of the general formula R4NHNH2 (V) (wherein R4 is as defined above) or an acid addition salt thereof, e.g., hydrochloride in a solvent, preferably ether or tetrahydrofuran, and optionally in the presence of a base, e.g. triethylamine or sodium acetate, at a temperature between 0 ° C and the boiling point of the solvent. When using: ·, an acid addition salt of a compound of general formula (V) is reacted with a compound of general formula (IV) with an alkali metal, e.g.

• I

'. in the presence of lithium, acetate, carbonate or bicarbonate.

25

According to another variant of process (c) (1), compounds of the general formula (I): ·: wherein R 2 is an S group, R 1 is a chlorine, bromine, iodine or fluorine atom or a cyano or the nitro group, and R 2 is an amino group, is also prepared by reaction of the corresponding 4-thiocyanatopyrazoles with an organometallic reagent, e.g., a compound of the general formula R 5 -MG-X 1 (VI) »wherein R is as defined above and χΐ is a halogen atom, in an inert solvent, such as diethyl ether or tetrahydrofuran, and at a temperature from -78 ° C to the reflux temperature of the reaction mixture, or with a compound of the general formula: 11415? 19 R 9 -OC-Li + (IX) wherein R 9 -OC 9 represents R 4 in formula (I) in an inert solvent such as tetrahydrofuran or diethyl ether at a temperature between -78 ° C and ambient temperature.

Alternatively, according to process variant (c) (2), compounds of general formula (I) wherein R 4 is a R 6 S group in which R 5 S is other than 1-alkenylthio or 1-alkynylthio may also be prepared by subjecting an intermediate which corresponds to general formula (I) wherein R 4 is replaced by a thiocyano group, by reaction with a base, preferably sodium hydroxide or a reducing agent, preferably sodium borohydride, in the presence of a reagent of general formula: R 5 '-X 2 (VII) wherein in the formula R 4 'is as defined above for R 4 with the exception of 1-alkenyl and 1-alkynyl, and X 4 is a halogen, preferably bromine or iodine, e.g. methyl) odide or propargyl bromide, or a base, preferably sodium hydroxide, with such a reagent in the presence of a general formula.

20 F2C = C (Z) Z '(VIIA)

i. I

wherein Z is a fluorine, chlorine or bromine atom and Z 'is as defined above for Z, or is a trifluoromethyl group, in an inert organic or aqueous organic solvent. , such as methanol, ethanol or dioxane, or a mixture of these solvents with water, the reaction being carried out at a temperature between -40 ° C and reflux temperature.

I i t-

Alternatively, according to process variant (c) (3), compounds of general formula (I) wherein R 1 S is other than 1-a-1; a benzylthio or 1-alkynylthio group by reductive alkylation of disulfides of general formula (VIII) using a reducing agent, preferably sodium dithionite or sodium borohydride, in the presence of a base, preferably sodium hydroxide or sodium carbonate, using iodide, in an inert organic or aqueous organic solvent such as ethanol, or in a mixture of alcohol and water, at a temperature between ambient temperature and reflux temperature.

114152 20

According to another variant (d) of the process, compounds of the general formula (I) having a R 6 -SO 2 group may be prepared by oxidation of the sulfur atoms of the corresponding alkylthio, alkenylthio or alkynylthio compounds of the formula (I) wherein R 10 is a hydrogen atom or a trifluoroacetyl, or preferably a 3-chlorobenzoyl group, in a solvent, e.g. dichloromethane, or a pharmaceutically acceptable salt thereof; in chloroform, or trifluoroacetic acid at 0-60 ° C, or with a reagent such as potassium hydrogen persulphate or potassium salt of Caron acid in a solvent, e.g. methanol and water, at a temperature between -30 ° C and + 50 ° C.

15

According to another modification of process (e), compounds of general formula (I) wherein R1 is a chlorine, bromine or iodine atom or a cyano or nitro group can be prepared by diazotizing an intermediate of general formula (I) wherein R1 is substituted the amino group and R 1 'have a hydrogen atom or an amino group using 20 sodium nitrite in a mineral acid, e.g. a mixture of concentrated sulfuric acid and acetic acid at a temperature of 0-60 ° C, followed by reaction with a copper salt and an aqueous solution of minic acid, potassium iodide at 0-100 ° C, or with cupric cyanide, or with sodium nitrite with a copper salt! in an inert solvent, e.g. water, at a pH of 1 to 7 at a temperature of 25 to 100 ° C. Alternatively, the diazotization may be carried out using an alkyl nitrite, e.g. tert-butyl nitrite, in the presence of a suitable halogenating agent, preferably bromo:: form or iodine or anhydrous cupric chloride, at a temperature of 0-100 ° C and optionally an inert solvent, preferably acetonitrile or in the presence of chloroform.

30: According to another variation of the process, compounds of general formula (I) wherein R1 is a fluorine atom and R1 is a hydrogen atom or an amino group can be prepared by diazotizing a corresponding amine substituted with an amino group using, for example, sulfuric acid solution of sodium nitrite or sodium: in the presence of 35 salts, followed by decomposition of the diazo with heat or light; nium fluoroborate derivative by methods known per se.

114152 21

According to another variant of process (f), compounds of general formula (I) wherein R1 is a fluorine atom or a cyano group and is a hydrogen atom or an amino group can be prepared by reaction of a halide of general formula (I) wherein R1 is chloro. or a bromine atom with an alkali metal fluoride, preferably cesium-5 fluoride, or a metal cyanide, preferably KCN, under anhydrous conditions in an inert solvent, preferably sulfolane, and at a temperature from about 150 ° C.

According to another modification of process (g), compounds of general formula (I) wherein R1 is a nitro group and R1 is a group R6SO can be prepared by reacting an intermediate of general formula (I) wherein R1 is substituted and R 4 is R 6 SO or R 6 S and is a hydrogen atom or an amino group reacted with an oxidizing agent, preferably trifluoro-peracetic acid or m-chloroperbenzoic acid, in an inert solvent, preferably 0 ° C and reflux temperature. In this process, simultaneous oxidation of sulfur can occur when R 1 is R 5 S.

According to another modification of process (h), compounds of general formula (I) wherein R1 is a cyano group and R1 is a hydrogen atom or an amino group can be prepared by dehydrogenating a compound corresponding to general formula (I) wherein R1 is replaced by a carbamoyl group . A compound of general formula (I), wherein R 1 is replaced by a carbamoyl group can be prepared by reacting a compound of general formula (I) where R 1 is replaced by a carboxy group; with a chlorinating agent, preferably thionyl chloride, at a temperature ranging from ambient to reflux, followed by reaction of the acid chloride intermediate with ammonia to produce the intermediate amide. Dehydration Direct? i; is usually carried out by heating with a dehydrogenating agent, e.g. phosphorus pentoxide or v: preferably phosphorus oxychloride, at a temperature of 50-250 ° C.

The alkali metal derivatives of the compounds of the general formula (I) (wherein R 1 represents an unsubstituted amino group) can be prepared by in situ reaction with an alkali metal, e.g. sodium or potassium, hydride in an inert aprotic solvent, e.g. dimethylformamide, at a temperature from the laboratory temperature to the reflux temperature of the reaction mixture.

j 35. Compounds of general formula (IA) wherein R 1 is a methyl group and R 4 is a hydrogen atom may be prepared by removing a group from R 1 C (= O) in a compound of general formula (IA) wherein R 4 is a methyl group, R 1 is a group RHC (= O) and 11415? R11 is a straight or branched chain alkyl or alkoxy group having 1 to 4 carbon atoms. Removal of R 11 (3 (= O)) can be accomplished by selective hydrolysis under mild conditions, e.g. by treatment with an hydroxide of an alkali metal such as sodium or potassium in water or an inert organic or aqueous organic solvent, e.g. lower alkanol such as methanol, or water. and a lower alkanol mixture at a temperature ranging from the laboratory temperature to the reflux temperature of the reaction mixture.

Compounds of general formula (IA) wherein R 1 is a methyl group and R 4 is a group R 10 (3 (= O) - can be prepared by: 1) reacting a compound of general formula (IA) wherein R is a hydrogen atom and R 4 is a group R 11 (3 (= O) or an alkali metal derivative thereof, eg sodium or potassium), with a compound of the general formula: R 15 -X 5 (XVI) wherein X 4 is chloro, bromine or iodine atom, wherein the reaction may be carried out in an inert organic solvent, e.g. dichloromethane, tetrahydrofuran or dimethylformamide, at a temperature ranging from laboratory temperature to the reflux temperature of the reaction mixture, and using a compound of general formula (IA), e.g. In the presence of Triton B, or; 2) reacting a compound of general formula (IA) wherein R 1 is a hydrogen atom and R 1 is a methyl group with a compound of general formula (XI) or (XII).

• <I

According to another embodiment (i) of the invention, compounds of general formula (I) wherein R 1 is a methylamino group may be prepared by reacting a compound of general formula (I) wherein R 1 is -N = CH (OR wherein R 1 is: a methyl group, with a reducing agent, preferably sodium borohydride. The reaction may be carried out in an inert organic solvent, with ethanol or methanol being most preferred, at a temperature from 0 ° C to the reflux temperature of the reaction mixture.

Compounds of general formula (I) wherein R 4 represents a halogen atom may be prepared by diazotization of the corresponding compound of general formula (I) wherein R 4 represents an amino group, using the aforementioned method (e), such compounds of general formula 35 114153 23 (I). for the preparation of compounds wherein R 1 is a halogen atom. The fluorides of general formula (I) wherein R 1 is a fluorine atom may also be prepared by a halide exchange reaction of the halides of general formula (I) wherein R 3 is a chlorine or bromine atom using the above process (f) Compounds of formula (I) wherein R 1 is fluoro.

According to another embodiment (j) of the invention, compounds of general formula (I) wherein R 1 is a hydrogen atom can be prepared by treating a compound of general formula (I) wherein R 1 is an amino group with a diazotizing agent, preferably tertiary butyl nitrite 11, preferably in tetrahydrofuran, at a temperature between ambient temperature and reflux temperature.

The intermediates of general formula (II) wherein R 8 is a cyano group can be prepared by diazotizing aniline R 1 -NH 2 (wherein R 1 is as defined above), usually in a solution of 1 molar equivalent of sodium nitrite in a mineral acid, e.g. a mixture of concentrated sulfuric acid and acetic acid at a temperature of 0-60 ° C, followed by reaction with a compound of the formula CH3COCH (Cl) CN Preparation described in J. Org. Chem. 43 3 (20) 3822 (1978) or with a compound of general formula CH 3 COCH (Cl) COCH 3 in the presence of an inert solvent, e.g. a mixture of water and ethanol, optionally; *. buffered e.g. using excess sodium acetate at 0-50 ° C.

*. ; Intermediates of general formula (I) wherein R 1 represents an amino group, R 4 represents a hydrogen atom and R * represents a cyano group can be prepared by diazotization of the aniline R 4 NH 2 (wherein R 4 is as defined above) generally using a solution, having 1: molar equivalent of sodium nitrite in mineral acid, e.g. a mixture of concentrated sulfuric acid and v: acetic acid, at a temperature of 0-60 ° C, and then reacting with a compound of the general formula: 30 '·': NC-CH 2 -CH (CO -R18) CN (XVII) '' wherein R18 represents an alkoxy group having 1 to 6 carbon atoms, preferably an ethoxy group, or a hydrogen atom, in the presence of an inert solvent, e.g. water and ethanol, optionally buffered e.g. sodium acetate, at temperature. 0-50 ° C. Subsequently, careful hydrolysis using a base such as aqueous sodium hydroxide, sodium carbonate or ammonia may be necessary to effect the cyclization.

11415? 24

The intermediates of the general formula (XVII) used above, wherein R 18 is a hydrogen atom, can be used as alkali metal enolate salts which can be converted to aldehydes under the acidic conditions of the above coupling reaction.

5

Intermediates of general formula (I) wherein R 1 is as defined above except for the formyl group, R 2 is replaced by a hydrogen atom and R 3 is an amino group can be prepared by decarboxylation of a compound of general formula (I) wherein R 2 is replaced by a carboxy group 100-250 ° C, optionally in the presence of an inert organic solvent, in particular N, N-dimethylaniline. Alternative intermediates of general formula (I) wherein R 2 is replaced by a hydrogen atom, R 1 is as defined above except for the formyl group and R 3 is an amino group may be prepared directly from esters of general formula (I) wherein R 2 is -COOR a straight or branched alkyl group of 1 to 6 carbon atoms by heating in an inert organic solvent, preferably acetic acid, at a temperature between 50 ° C and reflux temperature in the presence of a strong acid, preferably hydrobromic acid. When R 1 in this process is a chlorine or fluorine atom, simultaneous halogen exchange may also occur to provide intermediates wherein R 2 and R 3 are as defined above and R 1 is a bromine atom.

, ·; ·, Intermediate carboxy compounds of the general formula (I) wherein R 1 is. . as defined above with the exception of the formyl group, R 2 is replaced by a carboxy group; and R3 is an amino group can be prepared by hydrolyzing esters wherein R2 is substituted with -COOR, preferably using an alkali metal hydroxide in a solvent such as aqueous alcohol, at a temperature between 0 ° C and the reflux temperature of the reaction mixture.

Intermediate esters of general formula (I) wherein R 2 is replaced by a -COOR group as defined above, R 3 is an amino group and R 1 is a cyano or acetyl group may be prepared in the same manner as in the embodiment (a) described above. esters of ROOCCH 2 CN and intermediates of general formula (II) wherein R 4 is a cyano or acetyl group.

: 35 Intermediate esters of general formula (I) wherein R 2 is substituted with the above; with -COOR, R3 is an amino group and R1 is a chlorine or fluorine atom, can be prepared by the reaction of phenylhydrazine (V) with the general formula 11415? 25 (XVIII) wherein X, Y and R are as defined above, using Process Embodiment (c).

Alternative intermediates of general formula (I) wherein R 1 is chloro or fluoro, R 4 is replaced by hydrogen and R 4 is amino can be prepared by reacting the corresponding aldehydes wherein R 1 is substituted with a formyl group with an acid, preferably aqueous hydrochloric acid, in a solvent, preferably ethanol, at a temperature between 50 ° C and reflux temperature. Intermediates of general formula (I) in which R 4 is replaced by formyl-10 can be prepared by reacting nitriles in which R 4 is substituted with cyano group with a suitable reducing agent, preferably diisobutylaluminum hydride, in an inert solvent, preferably tetrahydrofuran. , at a temperature between -78 ° C and ambient temperature.

Intermediates of general formula (I) wherein R 4 is replaced by a cyano group may be prepared by reacting a compound of general formula (XIX) wherein X and Y are as defined above (i.e., dichlorodicyanoethylene or difluorodicyanoethylene) with phenylhydrazine ( V) as shown in embodiment (c).

20

Intermediates of general formula (XX) wherein R 19 is R 1 or a hydrogen atom. ·: ·. and R 4 is a hydrogen atom or an amino group, may be prepared by carrying out a Curtius remanufacture. grouping of a soene in an acid azide corresponding to general formula (I) wherein R1 '. ; is replaced by CON3 or is replaced by a hydrogen atom and R1 is replaced by * '*' 25 by CON3 by heating in an inert organic solvent such as toluene at 50-150 ° C to give the isocyanate which is then reacted e.g. butanol to obtain the carbamate, which in turn is hydrolyzed with dilute acid, preferably hydrochloric acid, in ethanol at a temperature between ambient temperature and reflux temperature.

30: '; The intermediate acid azides can be prepared by reacting a carboxylic acid of general formula (I) wherein R * is substituted with a carboxy group, and R 4 and R 6 are as defined above, with an azidine transfer reagent such as diphenylphosphoryl azide in a solution of triethylamine, 35 preferably in Ν, Ν-dimethylformamide at a temperature of 0 to 60 ° C.

Intermediate carboxylic acids in which R1 is replaced by a carboxylic acid group can be prepared by hydrolysis of the corresponding esters in which R1 is substituted by alkoxy. 26 with a base such as sodium hydroxide and a solvent such as aqueous alcohol at 0 ° C and the reflux temperature of the solvent.

Intermediate carboxylic acid esters wherein R * is an alkoxycarbonyl group and R ^ 9 is the same as r 2 can be prepared by reacting intermediate (XXI) wherein R and R 4 are as defined above and X 1 is a leaving group, e.g., a chlorine atom, with phenyl hydrazine. (VI) in the same manner as in Embodiment (c).

Alternatively, the intermediate carboxylic acid esters wherein R 1 is replaced by an alkoxycarbonyl group as defined above and R 1 is replaced by R 19 may alternatively be prepared in the same manner as in Embodiment (a) by reacting a compound (II) wherein R 5 is above, with a compound of the general formula R * 9CH 3 CN, wherein R 19 is as defined above. Intermediates of general formula (II) wherein R 4 is replaced by -COOR may be prepared from known compounds (e.g., CH 3 COCH (Cl) COOR) in the same manner as described above for compounds of general formula (II) wherein R 4 is cyano or acetyl group.

Intermediate halides of general formula (XXI) wherein R 1 is a chlorine atom and R 1 and R 2 are as defined above can be prepared by reaction of sodium or potassium salts (XXI) wherein R 1 is -0 "Na + or -0" K +. with a suitable chlorinating agent, preferably phosphorus oxychloride, in the presence of an inert solvent, e.g. tetrahydrofuran, at a temperature of 0 ° C and the reflux temperature of the solvent.

Intermediate salts (XXI) wherein R 1 'is -O'Na + or -O "K + can be prepared by the methods described in the acrylic compounds by reacting the active methylene compounds: *': R 1 CF 3 CN with dialkyl oxalates, e.g., diethyl oxalate, in the presence of a metal alkoxide, e.g., sodium ethoxide, in an inert solvent, e.g., an alcohol such as ethanol, at a temperature between 25 ° C and the reflux temperature of the solvent.

Intermediates of general formula (I) wherein R 1 is replaced by 1-hydroxyethyl may be prepared by reaction of aldehydes of general formula (I) wherein R 1 is: a 35 formyl group and R 4 is a hydrogen atom or an amino group, preferably with a Grignard reagent, preferably with methylmagnesium halide in an inert solvent, e.g. ether or tetrahydrofuran, at a temperature between ambient temperature and the reflux temperature of the solvent.

114153 27

Intermediate 4-thiocyanatopyrazoles of general formula (I) wherein R 4 is substituted with a thiocyano group and R 4 is an amino group can be prepared by reacting a compound of general formula (I) wherein R 4 is substituted with a hydrogen atom, with thiocyanic acid such as thi an alkali metal or ammonium salt (e.g., NaSCN) and bromine in an inert organic solvent such as methanol at a temperature of 0-100 ° C.

Intermediate disulfides of general formula (VIII) may be prepared by hydrolyzing 10-membered thiocyanates in which R1 is substituted by a thiocyano group and R1 is a chlorine, bromine or fluorine atom or cyano or nitro group using hydrochloric acid in the presence of ethanol or and reflux temperature. Alternatively, the thiocyanates can be converted to the compounds of general formula (VIII) by treatment with a base, preferably aqueous sodium hydroxide, and preferably under phase transfer conditions with chloroform as a co-solvent, and a phase transfer catalyst, e.g.

Intermediate diaminoesters of general formula (I) wherein R 1 and R 4 are an amino-20 group and R 4 is replaced by an ester group -COOR of 2 to 7 carbon atoms as defined above may be prepared by subjecting an appropriately substituted general formula (V) ,. of the phenylhydrazine of formula I with an alkali metal salt of alkyldicyanoacetate of the general formula.

ROOC-CH (CN) 2 (XXII) (where R is as defined above), preferably with potassium methyldicyanoacetate, using hydrochloric acid, between ambient and reflux.

The potassium salts of alkyldicyanoacetate can be prepared by reacting the corresponding al-30-alkyl chloroformate with maloninitrile in the presence of potassium hydroxide in tetrahydrofuran at a temperature of 0-100 ° C.

The intermediate diaminosulfonylpyrazoles of the general formula (I) wherein R 1 and R 2 are an amino group and R is a sulfonyl group R 1 SO 2 can be prepared in the same manner as described above by reacting phenylhydrazine (V) with a suitable alkylsulfonylmalonitrile, which has the general formula: 11415? 28 R5 SO2-CH (CN) 2 (XXIII) (wherein r5 is as defined above).

The preparation of compounds of general formula (XXIII) is described in the literature.

Intermediate esters of general formula (I) wherein R 1 is a chlorine, bromine or fluorine atom or a nitro group, R 1 is replaced by -COOR as defined above, and R 10 is an amino group can be prepared in the same manner as in embodiment (e) by diazotizing compounds of formula (I) wherein R1 is substituted with an amino group.

Intermediate esters of general formula (I) wherein R 1 is replaced by -COOR, R 1 is replaced by a hydrogen atom and R 1 is an amino group may also be prepared by reaction of phenyl hydrazine of general formula (V) with the general formula (XXIV) ), wherein M is sodium or potassium and R is as defined above. The reaction is carried out in an acidic medium, usually dilute sulfuric acid, optionally in the presence of a co-solvent, e.g. ethanol-20, and at ambient and the reflux temperature of the solvent.

. -; According to another embodiment of the invention there are provided intermediates of general formula (XXV), which may be used to prepare compounds of general formula (I) wherein R 1 'is the same as R 4' in formula (I) or is a hydrogen atom or a thiocyano group, and R 1 is the same as R 1 in formula (I) or is an amino or carbamoyl group. R ^ and R ^ in formula (XXV) have the same · · 'as in formula (I).

• I

5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole is a preferred intermediate.

The following examples and comparative examples illustrate the preparation of compounds of general formula (I) according to the invention: [Chromatographic treatment was carried out on a silica column (40/60 silica of May & Baker Ltd.) at 6.8 Nm 2 unless otherwise stated].

11415? 29

Example 1

Compounds n 1, 2, 3, 4, 5, 6, 7, 8, 9, 35.

A solution of 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole (20.0 g) in dichloromethane (100 mL) was magnetically stirred and treated dropwise with a solution of trifluoromethylsulfenyl chloride (10.08 g) in dichloromethane (50 mL) for 1 hour. The solution was stirred overnight at room temperature, then washed with water (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a solid (26.3 g). This solid was recrystallized from toluene / hexane to give 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) 4-trifluoromethylthiopyrazole as tan crystals (24.2 g), m.p. 169-171 ° C. By proceeding in a similar manner, but replacing 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole with the following appropriately substituted pyrazole, trifluoromethylsulphenyl chloride was obtained, unless otherwise stated: 5-amino-3 cyano-1- (2,6-dichloro-4-trifluoromethoxyphenyl) -4-trifluoromethylthiopyrazole, m.p. 125-126 ° C, as pale yellow crystals from 5-amino-3-cyano-1- (2,6-dichloro-20R-4-trifluoromethoxyphenyl) pyrazole; 5-amino-3-cyano-1- (2,6-dichloro-4-difluoromethoxyphenyl) -4-trifluoromethylthiopyrazole, m.p. 127-128.5 ° C, as a tan solid 5-amino-3-cyano-1-,? , (2,6-dichloro-4-difluoromethoxyphenyl) pyrazole; '. ; 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-difluoromethyl-thiopyracole, m.p. 159-161 ° C as a light brown solid from 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole and difluoromethylsulfenyl chloro; ::: 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-heptafluoropropylthiopyrazole, m.p. 148-150 ° C, after drying as a yellow solid in silica, eluting with dichloromethane and petroleum ether (2: 1) from 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole and *, heptafluoropropylsulfenyl ; 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-trichloromethyl-thiopyrazole, m.p. 245-247 ° C, after purification by chromatography as a white solid from 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -py. ratsolistajatrikloorimetyylisulfenyylikloridista.

11415? 30

The same procedure, but substituting trifluoromethylsulphenyl chloride for dichlorofluoromethylsulphenyl chloride and adding the corresponding molar amount of pyridine to the reaction mixture and stirring overnight, gave: 5-amino-3-cyano-4-dichlorofluoromethylthio-1- (2,6-d 178-180 ° C, after purification by chromatography and elution with diethyl ether / hexane (1: 1) as a white solid from 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole.

By the same procedure but using the corresponding molar amount of pyridine in the reaction mixture, 5-amino-3-chloro-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthio-pyrazole, m.p. 149-150.5 ° C, after recrystallization from hexane, 5-amino-3-chloro-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole as a white solid; 15-Amino-3-bromo-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole, m.p. 154-156 ° C, after recrystallization as a white solid from hexane / ethyl acetate and then hexane / cyclohexane from 5-amino-3-bromo-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole; 5-amino-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -3-fluoro-4-trifluoromethyl-thiopyrazole, m.p. 123-126 ° C, as a white solid starting from 5-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-fluoropyrazole; : ·. 5-amino-4-chlorodifluoromethylthio-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole, m.p. 167-168 ° C, starting from a white solid, starting from chlorofluoromethyl chloride! tyylisulfenyylikloridista. The product was purified by high performance liquid chromatography using an 8 micron irregular column (21.4mm x 25cm) eluting with acetonitrile / water (3: 2).

Comparative Example 1 The 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole used in the above example was prepared as follows: A suspension of nitrosyl sulfuric acid prepared from sodium nitrite (7.0 g). and concentrated sulfuric acid (27.5 ml), diluted with acetic acid (25 ml), cooled to 25 ° C and stirred mechanically. To this was added 2,6-dichloro-4-trifluoromethylaniline (21.2 g) in 35 acetic acid (50 ml) dropwise over 15 min at 25-32 ° C. This mixture was heated to 55 ° C for 20 min and added to a stirred solution of ethyl 2,3-dicyanopropionate (14.0 g) in acetic acid (60 ml) and water (125 ml) at 1020 ° C. After 15 min, water (200 mL) was added and the oily 114153 layer was separated. The aqueous solution was then extracted with dichloromethane (3 x 70 mL) and the resulting extracts were combined with oil and washed with ammonia solution (pH 9). The organic phase was then stirred with ammonia (20 mL) for 2 hours, after which dichloromethane-kenOS was separated. The layer was washed with water (1 x 100 mL), 5 1 N hydrochloric acid (1 x 100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give an oily solid. Crystallization from toluene / hexane gave the title compound as brown crystals (20.9 g), m.p. 140-142 ° C.

The same procedure, but substituting the appropriately substituted anilines for 2,6-dichloro-4-trifluoromethylaniline, gave: 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethoxyphenyl) pyrazole as a light tan solid. , m.p. 119-120.5 ° C, from 2,6-dichloro-4-trifluoromethoxy-15 cyaniline; 5-amino-3-cyano-1- (2,6-dichloro-4-difluoromethoxyphenyl) pyrazole after washing the first product, which was dissolved in dichloromethane, with saturated sodium carbonate solution. After recrystallization, the title compound was obtained from toluene as a yellow solid, m.p. 120.5-122.5 ° C, from 2,6-dichloro-4-difluoromethoxyaniline; 20-5-amino-1- (2-chloro-4-trifluoromethylphenyl) -3-cyanopyrazole as an orange crystalline solid, m.p. 133-135 ° C, from 2-chloro-4-trifluoromethylaniline; ,. 5-amino-3-cyano-1- (2,4,6-trichlorophenyl) pyrazole as a tan solid, m.p. 155-156 ° C, from 2,4,6-trichloroaniline; 5-amino-3-cyano-1- (2,6-dibromo-4-trifluoromethylphenyl) pyrazole as a yellow crystalline solid, m.p. 142-146 ° C, from 2,6-dibromo-4-trifluoromethylaniline; 5-amino-1- (2-bromo-6-chloro-4-trifluoromethylphenyl) -3-cyanopyrazole as a brown crystalline solid, m.p. 146-148 ° C, from 2-bromo-6-chloro-4-trifluoromethyl-1,1-aniline; 5-amino-1- (2-bromo-4-trifluoromethylphenyl) -3-cyanopyrazole as a yellow crystalline solid, m.p. 159-162 ° C, from 2-bromo-4-trifluoromethylaniline.

The 5-amino-3-chloro-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole used in Example 1 was prepared as follows: 35 A mixture of 5-amino-3-chloro-1- (2,6) -dichloro-4-trifluoromethylphenyl) -4-ethoxycycarbonylpyrazole (5.0 g) and hydrochloric acid (6 N; 75 ml) in glacial acetic acid (75 ml) were heated at reflux for 24 hours. The cooled reaction mixture was evaporated to a small volume and the pH was raised to 12 with sodium hydroxide (2 114153 32 N) and extracted with diethyl ether (3 x 75 mL). The resulting ether extracts were combined and evaporated in vacuo to give a mixture of 5-amino and 5-acetamidopyrazoles as a yellow gummy solid (3.5 g). This solid was dissolved in a mixture of hydrochloric acid (6 N; 30 mL) and dioxane (60 mL) and heated at reflux for 48 hours. The volatiles were removed in vacuo and the residue was purified by column chromatography using dichloromethane-hexane (4: 1). Evaporation of the eluate containing the parent compound gave the title compound (1.3 g), m.p. 128-129 ° C as a pale solid.

The 5-amino-3-chloro-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-ethoxycarbonylpyrazole used above was prepared as follows:

Tertiary butyl nitrite (15.0 g) was added dropwise to a stirred and cooled (0 ° C) mixture of 3,5-diamino-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-15 ethoxycarbonylpyrazole (50.0) g) and cupric chloride (21.0 g) in acetonitrile (600 mL) over 10 min. The reaction mixture was stirred for 2 hours at 0 ° C and for 2 hours at laboratory temperature, then evaporated to a small volume and poured into hydrochloric acid (5 N; 1500 ml). The resulting solution was extracted with dichloromethane (3 x 600 mL), washed with hydrochloric acid (2 N; 2 x 600 mL), dried over anhydrous magnesium sulfate and evaporated to give a brown gum. This tar-like substance was removed from the product using dry silica chromatography and, eluting with dichloromethane-hexane (4: 1), further purified on a chromatographic column using hexane containing increasing amounts of dichloromethane *. ; (60-80%) to give the title compound (15.8 g), m.p. 143-146.5 ° C, '* ·' in the form of an orange solid.

The 3,5-diamino-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-ethoxycarbonyl-pyrazole used above was prepared as follows: The potassium salt of ethyldicyanoacetate (35.2 g) was added to a stirred suspension of 2, 6-Dichloro-4-trifluoromethylphenylhydrazine (49 g) in hydrochloric acid (0.9 N; 220 ml) and the reaction mixture was stirred and refluxed for 18 h. The reaction mixture was then cooled to precipitate a solid which was filtered off with 250 ml of diethyl ether. ) and dried to give a pale solid (56 g) which was recrystallized from a mixture of ethyl acetate and hexane to give the title compound (29.2 g), m.p. 196-197 ° C, in the form of a pale solid. The potassium salt of ethyldicyanoacetate was prepared as follows: 11415.7 33

A solution of ethyl chloroformate (520 g) and maloninitrile (330 g) in tetrahydrofuran (500 ml) was added dropwise to the stirred solution of potassium hydroxide (560 g) and water (2.01) at a temperature below 40 ° C. (external cooling by ice). The reaction mixture was stirred at laboratory temperature for 15 h and then cooled to 0 ° C to precipitate a solid which was filtered off and dried over phosphorus pentoxide to give the title compound (334.4 g) as a light solid.

The 5-amino-3-bromo-1- (2,6-dichloro-4-trifluoromethyl-10-ylphenyl) pyrazole used in the above example was prepared as follows:

A mixture of 5-amino-4-carbethoxy-3-chloro-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -pyrazole (3.3 g) and hydrobromic acid (48%; 30 ml) in glacial acetic acid (50 ml), heated at reflux for 18 h. The mixture was evaporated to a low volume, made basic with sodium hydroxide solution (1 N) and the product was filtered off and dried (2.9 g). Recrystallization from a mixture of ethanol and water gave the title compound (2.5 g), m.p. 132.5-134 ° C as a colorless solid.

The 5-amino-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -3-fluoro-pyrazole used in the above example was prepared as follows. A mixture of 5-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-fluoro-4-formylpyrazole (1.5 g) in methanol (40 ml) and 2N hydrochloric acid (10 ml), heated to reflux; After evaporation in vacuo, water (100 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). The extract was washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo.

Purification by chromatography eluting with dichloromethane gave the title compound, m.p. 128-129 ° C, in the form of a white solid.

The 5-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-fluoro-4-formylpyrazole used above was prepared as follows: 35 A stirred solution of 5-amino-4-cyano (2 6-Dichloro-4-trifluoromethyl-phenyl) -3-fluoro-pyrazole (preparation described in PCT Patent Publication No. WO-8703-781-A) (2.2 g) in dry tetrahydrofuran (40 mL) was treated with a solution at -70 ° C under nitrogen. containing diisobutylaluminum hydride (13 mL; 11415 f 34 of 1 M toluene solution). The mixture was allowed to warm to room temperature over 2 hours, allowed to stand overnight, and poured into a mixture of 2N hydrochloric acid (50 mL) and ice (50 g). After stirring for 1/2 h, toluene (25 mL) was added and the organic layer was separated. The aqueous layer was re-extracted with dichloro-5-methyl methane (2 x 100 mL) and the combined organic solution was washed with sodium bicarbonate solution (20 mL) and dried over anhydrous magnesium sulfate. Evaporation in vacuo gave a brown solid (1.5 g) which was purified by chromatography and eluted with toluene / ethyl acetate (98: 2) to give the title compound (1.0 g), m.p. 137-139.5 ° C, in the form of a pale yellow solid.

10

Example 2

Compounds Nos. 10, 37.

To a mixture of sodium hydride (0.71 g of an 80% oil dispersion) in dry tetrahydrofuran (30 mL) was added 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole ( 4.0 g). After 20 min, 3 drops of 15-crown-5 were added and the mixture was cooled to 0 ° C. Methyl iodide (3.4 g) was then added and the mixture was stirred at 0 ° C for 1/2 h and then at room temperature overnight. The solvent was evaporated in vacuo and the residue partitioned between dichloromethane (80 mL) and water (80 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated in vacuo to give a pale yellow solid (4.29 g). Purification by chromatography eluting with dichloromethane. ; titanium / petroleum ether (1: 1) gave 3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -5-dimethylamino-4-trifluoromethylthiopyrazole (2.11 g), m.p. 109.5-110.8 ° C, '' in the form of a white solid.

v Following the same procedure, but substituting 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole 5-amino-3-cyano-1- (2,6- • 30 dichloro-4-trifluoromethylphenyl) -4-trifluoromethylsulfinylpyrazole and using dioxane as solvent and heating under reflux for 5 h gave 3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -5-dimethylamino-4-dimethylamino-4-dimethylamino-4 , m.p. 154-161 ° C in the form of a white solid.

11415? 35

Example 3

Compounds Nos. 11, 12.

A solution of 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole (4.0 g) in dry tetrahydrofuran (20 mL) was treated with tert-butyl nitrite ( 5.76 g) at room temperature. The mixture was then heated under reflux for 3 h and evaporated in vacuo to give a yellow solid.

Purification by chromatography eluting with petroleum ether / dichloromethane (2: 1) gave: 3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole (3.12 g), m.p. 126.5-128 ° C, in the form of a white solid.

15

By proceeding in a similar manner, but substituting the following phenylpyrazoles for 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole, 20 3-cyano-1- (2 6-dichloro-4-trifluoromethoxyphenyl) -4-trifluoromethylthiopyrazole, m.p. 64-65 ° C, in the form of a white solid, from 5-amino-3-cyano-1- (2,6-dichloro-4-, 4-trifluoromethoxyphenyl) -4-trifluoromethylthiopyrazole; 3-cyano-1- (2,6-dichloro-4'-trifluoromethylphenyl) -4-methanesulfonylpyrazole, m.p. 147-150 ° C, yellowish yellow; in the form of roads, from 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-methanesulfonylpyrazole.

> I J | I i

Example 4

Compound No. 13 30. To a solution of 3-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole (3.0 g) in dry acetonitrile (50 mL) was stirred at 0-5 ° C C and then at ambient temperature for 1/2 h, iodine (3.61 g) was added followed by tert-butyl nitrite (1.43 g). The solid was filtered off; 35 clubs, washed with dichloromethane (50 mL) and the combined filtrates washed with sodium thiosulfate solution (2 x 50 mL) and then water (50 mL). After drying over anhydrous magnesium sulfate, the solution was evaporated in vacuo to give a solid which was purified by chromatography eluting with petroleum ether / dichloro-114153 in 36 methane (2: 1). Recrystallization from toluene / hexane gave 1- (2,6-dichloro-4-trifluoromethyl-phenyl) -3-iodo-4-trifluoromethyl-thiopyrazole, m.p. 80-81.5 ° C, in the form of a white solid.

Comparative Example 2 The 3-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole used in the above example was prepared as follows: 10 3-tert-Butoxycarbonylamino-1- (2,6-dichloro 4-Trifluoromethylphenyl) -4-trifluoromethylthiopyrazole (3.45 g) dissolved in dry acetonitrile (80 mL) was treated with ioditrimethylsilane (2.6 g) added dropwise under a nitrogen atmosphere. After stirring for 45 min, methanol (10 mL) was added and after 15 min the solution was concentrated in vacuo to give a dark gum. This was dissolved in dichloro-15-methane (100 mL), washed with sodium sulfite solution (50 mL) and then water (50 mL) and dried over anhydrous magnesium sulfate. Evaporation of dichloromethane gave the title compound (2.6 g), m.p. 130-135 ° C as a pale solid.

The 3-tert-butoxycarbonylamino-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole used above was prepared as follows: *. 1- (2,6-Dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole-3-carboxylic acid (5.6 g) was dissolved in dry N, N-dimethylformamide (50 mL) and triethylamine (1.33 g) was added. ). After cooling to 5 ° C, a solution of diphenylphosphoryl azide (3.63 g) in N, N-dimethylformamide (20%) was added.

: =! mL). After reaching ambient temperature, the solution was heated to 35 ° C

v; For 2.5 hours. After evaporation in vacuo at a temperature below 40 ° C, a solution of sodium chloride (5 g) in water (100 ml) was added and the suspension was extracted with ether (3 x 100 ml). The combined extracts were washed with water (50 mL), dried over anhydrous magnesium; sulfate and evaporated to give 1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole-3-carboxylic acid azide (5.4 g). A solution of this in dry toluene (200 mL) was refluxed with stirring for 1.5 h, tert.butanol (35 mL) was added and reflux was continued for 4 h. After evaporation in vacuo, the residue was purified by chromatography eluting with dichloromethane to give the title compound. said compound (3.3 g) as a pale solid, m.p. 122-125 ° C.

114153 37 1- (2,6-Dichloro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-thiopyrazole-3-carboxylic acid, used above, was prepared as follows:

A solution of sodium hydroxide (1.73 g) in water (50 mL) was added to a suspension of 1- (2,6-dichloro-4-trifluoromethylphenyl) -3-ethoxycarbonyl-4-trifluoromethylthiopyrazole (6.8) g) in ethanol (70 ml) and the mixture was heated to reflux for 1 1/2 h. The solvent was evaporated in vacuo, water (250 ml) was added followed by concentrated sulfuric acid to pH 1. The product was filtered off, washed with water (100 ml) and dried at 120 ° C under vacuum to give the title compound (5.7 g) as a gray solid, m.p. 175-177 ° C.

The 1- (2,6-dichloro-4-trifluoromethylphenyl) -3-ethoxycarbonyl-4-trifluoromethylthio-pyrazole used above was prepared by the method of Example 3 by replacing 5-amino-3-cyano-1- (2,6-dichloro) -4-trifluoromethylphenyl) -4-trifluoromethyl-thiopyrazole with 5-amino-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -3-ethoxycarbonyl-4-trifluoromethyl-thiopyrazole. The title compound was obtained as a pale solid, m.p. 125.5-126 ° C.

The 5-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-ethoxycarbonyl-4-trifluoro-20-methylthiopyrazole used above was prepared according to the procedure of Example 1 and obtained as a white solid, m.p. 213-214 ° C, purification, followed by chromatography on 5-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -3- [beta] -ethoxycarbonylpyrazole. 5-amino-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -3-yl; ethoxycarbonylpyrazole was prepared as follows:

A solution of the sodium salt of 3-cyano-2-hydroxyprop-2-enoic acid ethyl ester: (50.0 g) [C.A. 57: 16604d NS Vulfson et al.] In cold water (500 mL) was stirred while cold sulfuric acid (2N) was added to pH 1. The solution was extracted with ether (2 x 400 mL) and the extract washed with water (200 mL). ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give a yellow oil (29.4 g). A solution of this in ethanol (400 mL) was treated with 2,6-dichloro-4-trifluoromethyl-. phenylhydrazine (51.1 g) and the solution was heated at reflux overnight.

After cooling, the solution was evaporated in vacuo to give an orange solid. Recrystallization from toluene / hexane afforded the title: 35 as a tan solid (40.2 g), m.p. 179-181 ° C.

t

Example 5 114153 38

Compounds # 14, 15, 16, 17, 18, 19, 20 5 Mixed solution of 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-thiopyrazole (10.0 g) in dichloromethane (100 ml) was treated with m-chloroperbenzoic acid (4.5 g). After stirring overnight, m-chloroperbenzoic acid (1.6 g) was added in two portions and the mixture was allowed to stand for 2 days. The reaction product was diluted with ethyl acetate (30 mL) and then washed sequentially with sodium sulfate solution (50 mL), sodium carbonate solution (50 mL), and water (50 mL). After drying over magnesium sulfate, the mixture was filtered and evaporated in vacuo. Purification from chromatography on silica eluting with dichloromethane gave 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylsulfinylpyrazole as a white solid, m.p. Mp 200.5-201 ° C.

Following the same procedure but substituting the above phenylpyrazole with the appropriate other phenylpyrazoles, there was prepared: 20 (2,6-dichloro-4-trifluoromethoxyphenyl) -4-trifluoromethylsulfinylpyrazole, m.p. 179-180 ° C, in the form of a white solid. Said compound was prepared from 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethoxyphenyl) -4-trifluoromethylthiopyric acid, using the appropriate amount of m-chloroperbenzoic acid; ',! t-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylsulfinylpyrazole, m.p. 142.5-144.2 ° C, in the form of a white solid, from 3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole and carrying out the reaction at 40-50 ° C. Within 20 h; • 1,5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) 4- (1-methylprop-2-ynylsulfinyl) pyrazole, m.p. 136.6137.2 ° C, in the form of a white solid; · 30-5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4- (1-methylprop-2-ynylthio); pyrazole; '. 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-methylsulfinylpyrazole, m.p. 176-177 ° C, in the form of light brown crystals from 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-methylthiopyrazole; : 35 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-isopropylsulfinyl: pyrazole, m.p. 187-188 ° C, in the form of a white solid, from 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-isopropylthiopyrazole; 11415? 39 5-amino-3-bromo-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylsulfonylpyrazole, m.p. 179-180 ° C, in the form of a white solid from 5-amino-3-bromo-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole.

Example 6

Compound No. 21.

A stirred mixture of 85% hydrogen peroxide (0.31 g) and dichloromethane (20 ml) was treated dropwise with trifluoroacetic anhydride (2.1 g) at -10 ° C. After 15 min, the mixture was allowed to warm to room temperature and stirred for an additional 15 min. After cooling to 0 ° C, a solution of 3-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole (1.0 g) was added [preparation described in Reference Example 4] dichloro -15 in methane (20 mL) and the solution was allowed to warm to room temperature. After 2 hours, trifluoro-peracetic acid (prepared as above using 85% hydrogen peroxide (0.31 g), dichloromethane (20 mL) and trifluoroacetic anhydride (2.1 g)) was added. The mixture was stirred overnight and then poured into water (50 mL), and the dichloromethane layer was washed successively with 5% sodium sulfite 20 solution (30 mL), sodium bicarbonate solution (30 mL) and water (30 mL). This solution was then dried over anhydrous magnesium sulfate and evaporated in vacuo. · Yielding a green gum (0.8 g). Purification by chromatography; elution with dichloromethane / hexane (3: 2) gave 1- (2,6-dichloro-4-trifluoromethylphenyl) -3-nitro-4-trifluoromethylsulfinylpyrazole (0.3 g), m.p. 124-130 ° C, '', 25 in the form of a light green solid.

·· << »• ·: 'Example 7

Compounds n 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 38.

;; · 30

A solution of 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-. thiocyanatopyrazole (3.1 g) in methanol (50 mL) was stirred under nitrogen at -7 ° C and methyl iodide (5.25 mL) was added. A solution of potassium hydroxide (0.92 g) in water (10 ml) was then added dropwise over 10 min keeping the mixture at a temperature below 0 ° C. After stirring at room temperature for 3 h, the mixture was neutralized; was added by addition of carbon dioxide spheres followed by water (180 ml). The precipitated solid was filtered off and recrystallized from toluene / hexane 11415? 40 (2: 1). 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-methylthiopyrazole was obtained as a brown crystalline solid (1.94 g), m.p. 170-172 ° C.

The same procedure but substituting the methyl iodide with the following alkyl-5 halides gave: 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-ethylthiopyrazole in the form of a yellow solid, m.p. 158-160 ° C using ethyl iodide and aqueous ethanol as solvent; 105-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-propylthiopyrazole in the form of a light brown solid, m.p. 123-124 ° C using propyl bromide and aqueous dioxane as solvent; 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-isopropylthiopyrazole as a light brown solid, m.p. 168-169 ° C using isopropyl 15 bromide and aqueous isopropyl alcohol as solvent; 5-Amino-3-cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4- (2-methyl-propyl-thio-pyrazole as a light brown solid, mp 134-137 ° C, using 1-iodo-di -2-methylpropane and aqueous dioxane as solvent; 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4- (1-methylpropyl-20-thio) pyrazole as a light brown solid, m.p. 5-154 ° C using 2-iodobutane and aqueous dioxane as solvent, The product was purified on a dry column of chromatography using silica eluting with hexane / diethyl ether (1: 1); 4-allylthio-5-amino-3-cyano-1- (2,6- dichloro-4-trifluoromethylphenyl) pyrazole as a light brown solid, mp 140-141 ° C, using allyl bromide and aqueous dioxane as solvent, the product was purified by chromatography eluting with hexane / diethyl ether (1: 1) and then re-crystallized; 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) li) -4- (prop-2-ynylthio) - 30 pyrazole as a brown solid, m.p. 161-163 ° C using propargylb:: romide and aqueous methanol as solvent; 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) 4- (1-methylprop-2-ynylthio) pyrazole as a white solid, m.p. 134-135.6 ° C, using 3-bromobut-1-yne and aqueous methanol as solvent, the product was purified by chromatography eluting with diethyl ether / hexane (1: 1) and then crystallized; re toluene / hexane; 5-amino-3-bromo-1- (2,6-dichloro-4-trifluoromethylphenyl) 4-methylthiopyrazole as a white solid, m.p. 117-119 ° C using methyl iodide and aqueous 11415.7 41 other methanol as solvent. The product was purified by chromatography eluting with dichloromethane.

By the same procedure, 5-amino-4- (2-chloro-1,1,2-trifluoroethylthio) -3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole, m.p. 116-118 ° C as a white solid using chlorotrifluoroethylene and aqueous dioxane as solvent. The product was purified by chromatography eluting with dichloromethane and then recrystallized from toluene / hexane (3:10).

Comparative Example 3 The 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-thiocyanatopyrazole used above was prepared as follows:

A suspension of potassium thiocyanate (4.99 g) in methanol (75 mL) was stirred at -78 ° C. Bromine (0.8 mL) dissolved in methanol (10 mL) was then added dropwise over 25 min. After 20 min, a solution of 5-amino-3-20 cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole (5.0 g) in methanol (50 mL) was added over 30 min. The mixture was stirred at -78 ° C and then allowed to warm to room temperature over 3 h before being poured into water (250 mL).

; v. The precipitated solid was filtered off, washed with water and recrystallized; toluene / hexane to give the title compound (3.1 g) as a white solid, m.p. 179-182 ° C.

: In the same manner as in the fishing line, but substituting 5-amino-3-cyano-1- (2,6-dichloro-4'-trifluoromethylphenyl) pyrazole in the above comparative example 5-amino-3-bromo-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole gave: 5-amino-3-bromo-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-thiocyanatopyrazole as a white solid, m.p. 162-163.5 ° C, after purification by chromatography eluting with dichloromethane.

: 35 Preparation of 5-amino-3-bromo-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole, m.p. was used above, is described in Comparative Example 1.

Example 8 42 11415.7

Compound No. 32.

To a stirred solution of 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-thiocyanatopyrazole (5.0 g) in dry diethyl ether (70 mL) at 0 ° Under nitrogen atmosphere, a solution of tert-butylmagnesium chloride (7.92 mL of a 2M solution in dry ether) was added dropwise. The solution was then allowed to warm to room temperature and stirring continued for 3 h. Water (40 mL) was then added and the mixture stirred for 15 min. The ether layer was separated, washed with water (50 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo to give a brown solid. Purification by chromatography eluting with dichloromethane / petroleum ether (3: 1) gave 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-tert-butylthiopyrazole (2.62 g), m.p. 196-198.5 ° C, balance 15 in the form of a pale yellow solid.

Example 9

Compound No. 33 20

A solution of 5-amino-3-bromo-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-. methylthiopyrazole (2.0 g) [prepared as described in Example 15] methano. , ·. (45 ml) at -25 ° C was treated by the rapid addition of potassium hydrogen persulphate! solution of phate (1.66 g) followed immediately by water (22 ml). The mixture was stirred at 0 ° C for 30 min and potassium hydrogen persulfate (0.4 g) was added. After stirring for 2 1/2 hours at room temperature, the mixture was poured into water (300 mL) and; : saturated sodium bisulfite solution (35 mL) was added. This was extracted with dichloromethane (2 x 150 mL) and the extract was washed with water (2 x 50 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The crude product was purified by chromatography eluting with dichloromethane / ethyl acetate (4: 1) to give 5-: amino-3-bromo-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-methylsulfinylpyrazine; sol (0.9 g) as a white solid, m.p. 135-136 ° C.

11415? 43

Example 10

Compound No. 34 A solution of 3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -5-ethoxymethyleneamino-4-trifluoromethylthiopyrazole (1.7 g) in methanol (30 mL) was stirred. and sodium borohydride (1.08 g) was added portionwise. The solution was allowed to warm to room temperature and then poured into water (200 mL) for 7 h. This was extracted with dichloromethane (3 x 50 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo to give a white solid (1.4 g). Purification by chromatography eluting with dichloromethane / petroleum ether (4: 1) gave 3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -5-methylamino-4-trifluoromethylthiopyrazole (0.42 g) as a white solid, m.p. . 208.5-209.5 ° C.

15 Example 11

Compound No. 36

A solution of pentafluoroethyl iodide (5.0 g) in dry ether (30 mL) was stirred at -78 ° C while a solution of phenylmagnesium bromide (0.02 mol) in dry ether (20: 1) was added dropwise. ml), and a separate solution of 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-thiocyanatopyrazole (7.6 g) in dry ether (75 ml), , Within 5 hours.

The mixture was allowed to warm to room temperature and treated after 0.5 h with * 25 hydrochloric acid solution (2 M, 15 mL) at 0 ° C. The ether layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give a brown gum (8.8 g). Purification by dry column chromatography using v: eluting with dichloromethane / petroleum ether (1: 1) gave 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-pentafluoroethylthiopyrazole, m.p. 134.5-30 136.5 ° C as a yellow solid.

Example 12

Compounds # 1, 7 and Intermediate in Comparative Example 2.

: 35; To a stirred solution of 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) pyrazole (2.23 g) and pyridine (0.55 g) in chloroform (50 mL) , a solution of trifluoromethylsulfenyl chloride (1.24 11415.7 g, 44 g) in chloroform (15 mL) was added dropwise at 0 ° C over 20 min. The mixture was stirred at 0 ° C for 3 h and the solvent evaporated in vacuo to give a yellow solid (3.1 g). This was purified by chromatography on a column of silica (Merck, 230-400 mesh; 0.7 kg cm 2) eluting with dichloromethane and petroleum ether b.p. 40-60 (3: 1) to give 5-amino-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -3-cyano-4-trifluoromethyl-thiopyrazole as a white solid (2.33 g). , m.p. 169.5-170.5 ° C.

By proceeding in a similar manner, but substituting the following phenylpyrazoles for 5-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-cyanopyrazole, 10-5-amino-3-bromo-1- (2,6- dichloro-4-trifluoromethylphenyl) -4-trifluoromethylthiopyrazole as a colorless solid, m.p. 154.5-156 ° C from 5-amino-3-bromo-1- (2,6-dichloro-4-trifluoromethylphenyl) -pyrazole; 5-Amino-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-trifluoromethyl-thiopyrazole-3-15-carboxylic acid ethyl ester as a white solid, m.p. 213-215 ° C from 5-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-ethoxycarbonylpyrazole.

The 5-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-ethoxycarbonylpyrazole used in the above example was prepared as follows:

A solution of the sodium salt of 3-cyano-2-hydroxyprop-2-enoic acid ethyl ester: ·. (50.0 g) in cold water (500 mL), stirred and acidified to pH 1 with sat. v. with dilute sulfuric acid. Sodium chloride (50 g) was then added and the solution was extracted with ether (2 x 200 mL). This extract was washed with water (50 mL), dried (anhydrous magnesium sulfate) and evaporated to give a yellow liquid (30.2 g). This was dissolved in ethanol (400 mL) and stirred while rapid addition of 2,6-M: dichloro-4-trifluoromethylphenylhydrazine (52.5 g). The solution was heated to reflux; After refluxing overnight, it was cooled and evaporated in vacuo to give an orange solid. After trituration with hexane (300 mL), the filtered solid was recrystallized from toluene-hexane charcoal: to give the title compound (43.4 g), m.p. 177-179 ° C, obtained as light brown crystals.

Comparative Example 4: 35: A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (10.1 g) in tetra-

hydrofuran (50 mL) was stirred at room temperature and potassium carbonate (anhydrous; 8.5 g) was added. To this was added dropwise at 0 ° C

11415? A solution of 2-chloro-3-cyano-3- (1-methyl) ethylsulfonylprop-2-enoic acid ethyl ester (11.0 g) in tetrahydrofuran (100 mL). After stirring for 2 h, the mixture was filtered and the filtrate evaporated in vacuo to give a brown oil. After trituration with hexane (100 mL), a white solid (11.7 g) was obtained. After refluxing in ethanol and cooling, 5-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-ethoxycarbonyl-4- (1-methyl) ethylsulfonylpyrazole (8.5 g), m.p. 255.5-256.5 ° C, as white crystals.

Comparative Example 5 The 2-chloro-3-cyano-3- (1-methyl) ethylsulfonylprop-2-enoic acid ethyl ester used above was prepared as follows: 3-Cyano-2-hydroxy-3- (1-methyl) ethylsulfonylprop-. The sodium salt of 2-acetic acid ethyl ester (10.0 g) was added to stirred phosphorus oxychloride (28.5 g) at room temperature. After 3 h, the mixture was heated at 50 ° C for 1 h and then evaporated in vacuo. The residue was re-evaporated after addition of toluene to give the title compound as a brown oil.

The sodium salt of 3-cyano-2-hydroxy-3- (1-methyl) ethylsulfonylprop-2-enoic acid ethyl ester was prepared as follows:. A solution of sodium ethoxide (4.0 g) in sodium (4.0 g) and ethanol (80 ml) was treated with propane-2-sulfonylacetonitrile (24.5 g) with stirring.

When dissolution was complete, diethyl oxalate (24.8 g) was added dropwise over 10 min to give a heavy precipitate. After heating under reflux for 1 h, the yellow solid was filtered, washed with hexane and dried in a vacuum desiccator (41.3 g). This was the title compound, m.p. 195-197.5 ° C.

Example 13

Compounds # 20 and # 14 and intermediate # 14.

: 35; Proceeding in the same manner as described below, but replacing 5-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-methylthio-3-trifluoromethyl-pyrazole with the following phenylpyrazoles, afforded: 11415346 5-amino-1- (2,6-Dichloro-4-trifluoromethylphenyl) -3-ethoxycarbonyl-4-trifluoromethylsulfmylpyrazole as a white solid, m.p. 210-214 ° C from 5-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-ethoxycarbonyl-4-trifluoromethylthio-pyrazole; 5-Amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-bromo-4-trifluoromethylsulfonylpyrazole as a white solid, m.p. 179-180 ° C from 5-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-bromo-4-trifluoromethylthiopyrazole; 5-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylsulfonylpyrazole as a white solid, m.p. 203-203.5 ° C from 5-amino-1- (2,6-10 dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole.

A stirred solution of 5-amino-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-methyl-thio-3-trifluoromethyl-pyrazole (1.0 g) in chloroform (40 mL) was treated with m-chloroperbenzoic acid (0.42). g) added portionwise at room temperature. After stirring for 6 h, the solution was diluted with dichloromethane and washed sequentially with sodium sulfite solution, sodium hydroxide solution and water. The solution was dried over anhydrous magnesium sulfate and evaporated in vacuo to give a yellow oil. Purification by chromatography on silica (Merck, 230-400 mesh; 0.7 kg cm -1) eluting with dichloromethane ethyl acetate (4: 1) gave 5-amino-1- (2,6-20 dichloro-4-trifluoromethylphenyl) -4-methylsulfinyl-. 3-trifluoromethylpyrazole as a white solid, m.p. 142-145 ° C (dec.).

Comparative Example 6 '25 5-Carbamoyl-4-cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -3-trifluoromethyl-pyrazole (3.57 g) was heated to 200 ° C with phosphorus pentoxide (2.82 g). while stirring. After 3 h, the cooled product was treated with ice v and extracted with dichloromethane (3 x 50 mL). The organic solution was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a solid. Recrystallization from hexane gave 1- (2,6-dichloro-4-; trifluoromethylphenyl) -4,5-dicyano-3-trifluoromethylpyrazole as white crystals. (1.8 g), m.p. 80 ° C.

Proceeding in the same manner as described above, but substituting 5-carba-: 35-moyl-4-cyano- 1- (2,6-dichloro-4-trifluoromethyl-phenyl) -3-trifluoromethyl-pyraz; sol with 5-amino-3-carbamoyl-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-methanesulfonyl-pyrazole, prepared: 114153 47 5-amino-3-cyano-1- (2,6-dichloro) 4-trifluoromethylphenyl) -4-methanesulfonyl-pyrazole as a white solid, m.p. 214 ° C.

Comparative Example 75 The 5-carbamoyl-4-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-trifluoromethylpyrazole used in the above Comparative Example 10 was prepared as follows: 105 5-Carboxy-4-cyano. 1- (2,6-Dichloro-4-trifluoromethylphenyl) -3-trifluoromethyl-pyrazole (6.0 g) was added to thionyl chloride (30 mL) and the stirred solution was refluxed for 4 h. The solvent was evaporated in vacuo and evaporated again to dry toluene (30 mL) ) after adding. The resulting orange oil was dissolved in dry ether (10 mL) and added dropwise to a stirred ammonia solution (0.88; 20 mL) which was cooled in an ice bath. After stirring overnight, water (150 mL) was added and the mixture was extracted with dichloromethane (3 x 50 mL). The combined extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a white solid (7.0 g). Recrystallization from a mixture of ethyl acetate and petroleum ether gave the title compound (4.3 g) as white crystals, m.p. 180-181 ° C.

, 5-amino-3-carbamoyl-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -4-methanesulf; . The phenylpyrazole used in Comparative Example 6 above was prepared. ! by the same method but substituting 5-carboxy-4-cyano-1- (2,6-dichloro-4 '' trifluoromethylphenyl) -3-trifluoromethylpyrazole 5-amino-3-carboxy-1- (2,6-di- chloro-4-trifluoromethylphenyl) -4-methanesulphonylpyrazole. The title compound was obtained as a light solid, m.p. 223-224 ° C.

The 15-amino-3-carboxy-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-methanesulfonyl-30-pyrazole used above was prepared as follows: 5-amino-1- (2,6) -dichloro-4-trifluoromethylphenyl) -3-ethoxycarbonyl-4-methanesulfonylpyrazole (8.15 g; Reference Example 3) was added to stirred 80% sulfuric acid (80 ml) and heated at 100 ° C for 5 h. The solution was poured onto ice, the solid separated by filtration and dried over phosphorus pentoxide in a vacuum desiccator. Recrystallization from a mixture of methanol and petroleum ether gave the title compound as a white solid, m.p. 203-205 ° C.

11415c 48 a2 ^^ r1 jr% k *

Cl R8 ^ C = NSHR4 (II) E \ (17) 2ΚΓ ^ Y - S ~ 7j-T-R1

I i * I

R yr r1; iViA ^ (IA): • jV * '; R12R12N- <rN (IB)

U

R *

ROOCv X

: XC = C ^ (X7III)

NC ^ T

i NC X

> = C. (XIX)

2KK Y

49 11415?

U

R *

R2 COOR

XG = CX (XXI)

HC ^^ X6 H COOR

^ c = cr (xn?) NC ^ M + r2 ~ T ~ Tk

X; U

Claims (3)

11415c 50 1. For the formulation of N-phenylpyrazolder, a therapeutic form, which may be formulated as follows: 3 K • \ R | i .: ': R 4 (I) * * t' 'R 1 is a cyano-alkyl nitrogen group halogen atom, R2 is a group R5SO eller R5S, i is a group R5 is an enantiomer of alkyl, alkenyl-eller alkenyl group som har högst 4 kolatomer och som kan ester substitution substituents eller: substituents med en eller flera halogenatomer, wannan kan valks likadana eller olika, R3 is unsubstituted eller en amino-eller methylamino group. 2,6-Dichloro-4-trifluoromethyl-methyl-2,6-dichloro-4-trifluoromethoxyphenyl; (A) da R2 and R5SO eller R5S, R3 is an amino group and R1 is a cyano group, the title compound is formed in the form of Cl 114153 53 ^ C ^ NNHR4 / R8 (II) and R8 is a cyano group; and R4 is an amino acid methylene group, (b) da is R5S and R3 is an amino-methyl methyl group, and is a 5-membered amino acid form (R) CH2CN; I), the substituents of R 2 are unsubstituted, R5-SC1 (III), the definitions of R5 are 9 Cl (c) (1) as R is Group R, R is chloro, bromo, iodo-alkyl, fluoro-eller, 10-cyano-alkyl nitrogroup and R3 is amino group, form I (I) , the substituents of the R 2 substituent on the thiocyanate group, R 5 -MG-Xl (VI) are defined on the basis of R 5-Mg-X 1 (VI), and the halogen atom of the R 5 is: R 9 -OC "Li + (IX) *,; ????????? R 9 -C 6 C ?????????? R 9 -C ^ C is a moiety R 5 ????????? R 5 ????????? ???????? (c) (2) ??? - Ell '' -L-alkynylthio group, latten en förening med den allmänna formeln (I), i wears R:.:: 20 substituerats med en thiocyanatogrupp, reagent med en bas eller et reduktionsmedel i ::: nerve agent av en reagent med den allna. formeln:.; R5-X2 (VII) -, -, - - - - - - - - - - - - - - - (R-X2) (VII) -, -, - - - - - - - - - - - (INCH) -CH2 -CH2; bas i Nervous system, for example, 25 den allmänne formeln:: V: F2C = C (Z) Z '(VIIA) i fused with Z, fluorine, chlorine bromine and Z' and moss som Z eller en trifluor -methyl group, 114153 54 (d) da r R a group R SO, oxidering av en svavelatom i förening med denomannne formeln (I), R 1 or R 5 S, (e) da R 1 fluoro, chloro, the iodine-bromo-atom, or the cyano-eller, nitrogroup, diazotization of the amino substituent (I), and the substituent of the R 1 substituent o the medial amino group and the amino group, and omvandling of the diazoterade amino group R 1. a förfaranden account for fluorine, chlorine, bromine-iodine eller en cyano-eller nitrogroup, (f) da R1 is fluorine eller en cyanogroup och R3 is unsubstituted eller en amine group, latten halide med den allmänna formeln (I) , in the presence of R1, chlorobenzene 10 bromine, reactant alkali metal fluoride eller metal cyanide for the chloroformate bromomethyl bromide i is a fluorine eller or a cyano group, (g) da r is an nitrogroup and a R is a group R SO, is a salt of R 1 substituent med en amino group and R 2 is a R 5 SO eller R 5 S and R 3 is the amino group of the reagent, the reactant med that is oxidationmed for the amino group of the nitrile group R1, (h) the cyano group of the amino group, the dehydration of the amino group (I), and the R1 a substituent med en carbamoyl group, (i) da R3 methyl methyl group, fatty acid derivative form I (i), i 20 R3 group N-CH (OR17), i R17 methyl group, reagent ett reduktionsmedel eller (j) da R &lt; tb &gt;, l &apos; &lt; / RTI &gt; Formula (I), I am R &lt; 1 &gt; amino group, reactant med et diazoteringsmedel i et lösingings frän omgivningens Temperature account 25 pen R3 account no pretense,; , som eventuellt fukors av omvandling av den erhällna föreningen med den allmänna '' formeln (I) account i give förening med den allmänna formeln (I). A process for the preparation of a therapeutically active N-phenylpyrazole derivative of the general formula: wherein R 1 represents a cyano or nitro group or a halogen atom, R 2 represents a group R 5 SO or R 5 S in which R 5 represents a straight or branched chain alkyl -, an alkenyl or alkynyl group having up to 4 carbon atoms, which may be unsubstituted or substituted by one or more halogen atoms, which may be the same or different, R3 is a hydrogen atom or an amino or methylamino group and R4 is a 2,6-dichloro-4-trifluoromethyl or 2,6-dichloro-4-trifluoromethoxyphenyl group, characterized in that it comprises (a) when R2 is a group R5SO or R5S, R3 is an amino group and R1 is a cyano group of a compound of the general formula: ci: * - 'VS'C = NNHR4 / 15 R1 (II) 4 :. - wherein R is a cyano group and R is as defined above, with a compound of the general formula R 2 CH 2 CN wherein R 2 is as defined above, (b) when R is a group R 5 and R is an amino or methylamino group, reacting a compound of general formula (I) wherein R 2 is replaced by a hydrogen atom with a compound of general formula: R 5 -SC 1 (III) wherein R 5 is as defined above, (c) (1) when R 2 is a group R 5 S, R1 is a chlorine, bromine, iodine or fluorine atom or cyano; or a nitro group, and R 3 is an amino group, reacting a compound of general formula (I) wherein R 2 is substituted with a thiocyano group with a compound of general formula: 11415? R5-Mg-X '(VI) wherein R5 is as defined above X1 is a halogen atom or with a compound of the general formula R9-OC-Li + (IX) 5 wherein R9-C I), (c) (2) when R 2 is a group R 5 S wherein R 5 S is other than 1-alkenylthio or 1-alkynylthio, reacting a compound of general formula (I) wherein R is substituted with a thiocyanatory group with a base or a reducing agent in the presence of a reagent of the general formula: R5'-X2 (VII) wherein R5 is as defined above for R5 except for 1-alkenyl and 1-alkynyl and X2 is a halogen atom, or with a base in the presence of a compound of the general formula: F2C = C (Z) ) Z '(VIIA) wherein Z is a fluorine, chlorine or bromine atom and Z' is the same as Z or is a trifluoromethyl group, (d) when R 2 is a group R 5 SO, oxidation of the sulfur atom according to general formula (I): in a compound wherein R 1 is a group R 5 S, • ': (e) when R 1 is a fluorine, chlorine, iodine or bromine atom or a cyano or nitro group, the general::: compound of formula (I) wherein R is substituted with an amino group and R is hydrogen *; atom or amino group, converting diazotized and diazotized amino group R1: by known methods to a fluorine, chlorine, bromine or iodine atom or cyano or nitro group, (f) when R1 is a fluorine atom or cyano group and R3 is a hydrogen atom or amino group, reacting a halide of general formula (I) wherein R 1 is a chlorine or bromine atom with an alkali metal fluoride or metal cyanide to convert a chlorine or bromine atom to a fluorine atom or cyano group: (g) when R 1 is a nitro group and R 2 is a R 5 A compound of formula (I) wherein R 1 is substituted with an amino group and R 2 is a group R 5 SO or R 5 S and R 3 '. 30 is a hydrogen atom or an amino group, reacting with an oxidizing agent to convert an amino group to a nitro group R1, f1 ·. λ (h) when R is a cyano group and R is a hydrogen atom or an amino group, dehydrating a compound of general formula (I) wherein R 1 is substituted with a carbamoyl group; (i) when R 3 is a methylamino group of a compound of general formula (I) is reacting a group -N = CH (OR17) wherein R17 is a methyl group with a reducing agent, or -V (j) when RJ is a hydrogen atom, reacting a compound of general formula (I) wherein R is an amino-5 group with a diazotizing agent in a solvent, from ambient temperature to reflux, to convert the amino group R3 to a hydrogen atom, optionally followed by conversion of the compound of general formula (I) thus obtained into another compound of general formula (I). Process according to Claim 1, characterized in that R 1 is a cyano or nitro group. Process according to Claim 1, characterized in that 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylsulfonylpyrazole is prepared. 15 Patent Claims 2. Förfarande enligt patent krav 1, kanknetecknat av att R1 and en cyano-nitrogroup. 30 5-amino-: 3-cyano-1- (2,6-dichloro-4-trifluoromethylphenyl) -4-trifluoromethylsulfinylpyrazole.