CS268823B2 - Fungicide and method of active substances production - Google Patents

Description

The invention relates to novel thio compounds and to a process for their preparation. The invention furthermore relates to fungicidal compositions, in particular soil or seed treatment compositions for protection against phytopathogenic microorganisms, which compositions contain the aforementioned novel compounds as active ingredients. Finally, the invention describes the use of the above compositions in agriculture and horticulture.

Nitrothiazoles having fungicidal activity, for example used for seed treatment, are known from OE-OS No. 2,627,328. In this application, 2-methylsulfinyl-4-methyl-5-nitrothiazole is described as active substance. However, as will be apparent from the examples below, this compound has proven to be ineffective in practice.

Nitrothiophenes having fungicidal activity, particularly intended for the treatment of seed or soil against phytopathogenic microorganisms, are described in U.S. Pat. No. 4,451,660. In this patent, 2-methylsulfinyl-3-nitrothiophene and 2-ethylsulfinyl-3 are described as specific compounds. -nitro-5-acetylthiophene. However, it has now been found that even the efficacy of these compounds is not suitable in practice. Moreover, these compounds exhibit undesirable toxicity to warm-blooded animals.

It is an object of the present invention to provide novel thio compounds with improved fungicidal activity, in particular against phytopathogenic fungi infecting plant seeds and soil fungi, and with lower toxicity to warm-blooded animals. This requirement is met by the novel thio compounds according to the invention which correspond to the general formula I

OF

R

(I) in which

^R 2 represents a C 1 -C 12 alkyl group, a C 2 -C 4 alkenyl or alkynyl group, a phenyl group or a benzyl group; substituted benzoyl or C 1 -C 4 alkylsulfonyl, is hydrogen, halogen, amino optionally substituted by one or two substituents selected from C 1 -C 4 alkyl and C 2 -C 5 alkylcarbonyl, triazolyl a group, imidazolyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy optionally substituted with C 2 -C 5 alkylcarbonyl, phenyl optionally substituted with halogen, phenoxy or phenylthio, or

R 1 and R ₂ together with the vinylene group to which they are attached form a phenyl group optionally substituted by halogen or nitro group,

X is cyano or formyl, β is 1 or 2,

Y is C 1 -C 4 alkylthio;

Z represents a hydrogen atom or a halogen atom, or

Y and Z together represent a sulfur atom, with the proviso that if Y and Z do not together represent a sulfur atom, they form a and R ^ together with the vinylene

CS 268823 82 to which they are attached, a phenyl group optionally substituted by one or two halogen atoms.

Of the above compounds, thio compounds corresponding to formula II 'are preferred.

in which

R * represents an alkyl group having 1 to 4 carbon atoms,

Y * is C 1 -C 4 alkylthio;

Яд represents a hydrogen atom or one or two halogen atoms as well as thiophenes of the general formula III

(III) wherein

R, Rp, R ₂ , X and n are as defined above.

The compounds of the first group, i.e. the compounds of formula II, may exist in two stereoisomeric forms, namely in the Z-form (cis-form) and the E-form (trans-form), and of course in the form of mixtures of these stereoisomers in the any ratio. If desired, these isomers may be separated by known techniques. The steric configuration may affect the activity of the compound in question.

Among the second group of compounds, i.e. the group of compounds corresponding to formula III, the compounds of formula IV are preferred

CS 268823 81 (IV)

in which

R 1 is cyano, formyl, C 2 -C 5 alkylcarbonyl or benzoyl optionally substituted with halogen and n, R 2 and R 2 are as defined above, or wherein

R 1 and R ₂ together with the vinylene group to which they are attached form a phenyl group optionally substituted by halogen or nitro group,

Of the latter group of compounds, compounds of formula V have been shown to be excellent fungicides

(IV) wherein

R @ 1 represents a C1 -C4 alkyl group, a cyano group, a formyl group, an acetyl group, an unsubstituted benzoyl group or a benzoyl group substituted with one or two halogen atoms, and

R? represents a hydrogen atom, a halogen atom, an alkyl or alkoxy group each containing 1 or 2 carbon atoms or an amino group optionally substituted by a methyl group.

Examples of novel thio compounds of the invention include the following:

(1) 2-methylsulfinyl-3-cyano-5-acetylthiophene, (2) 2-methylsulfinyl-3-cyano-4-chloro-5-acetylthiophene, (3) 2-methylsulinyl-3,5-dicyano-4- chlorothiophene, (Д) 2-methylsulfinyl-3,5-dicyanthiophene, (5) 2-ethylsulfinyl-3-cyano-4-chloro-5-acetylthiophene, (6) * 2-methylsulfinyl-3-cyano-4- ( 4-chlorophenyl) -5-acetylthiophene, (7) 2-ethylsulfinyl-3,5-dicyano-4-chlorothiophene, (8) 2-ethylsulfinyl-3,5-dicyanthiophene, (9) 2-ethylsulfinyl-3-cyano75 (10) 2-ethylsulfinyl-3-cyano-4-amino-5-acetylthiophene, (11) 2-methylsulfinyl-3-cyano-4-chlorobenzothiophene, (12) 2-methylsulfinyl-3,5-dicyano- 4-methoxythiophene, (13) 2-ethylsulfinyl-3,5-dicyano-4-methoxythiophene, (14) 2-ethylsulfinyl-3,5-dicyano-4-ethoxythiophene, (15) -cyan-O-methylsulfinyl-O- methylthio-3,4-dichlorostyrene, (16) 2-ethylsulfonyl-3,5-dicyanthiophene, (17) 2-ethylsulfinyl-3-cyano-4-N-methylamino-5-acetylthiophene, (18) 2-ethylsulfonyl-3 -cyan-4-chloro-5-acetylthiophene, (19) -cyan-O-methylsulfinyl-C-methylthio-4-chlorostyrene, (20) 2-ethylsulfinyl-3-cyano-6-chlorobenzene zothiophene, (21) 2-ethylsulfonyl-3-cyano-5-acetylthiophene, (22) 2-ethylsulfonyl-3,5-dicyano-4-chlorothiophene, (23) 2-ethylsulfinyl-3-cyano-4-methoxy-5 -acetylthiophene, (24) 2-propargylsulfinyl-3,5-dicyano-4-methoxythiophene, (25) 2-methylsulfinyl-3-cyano-4-methoxy-5-acetylthiophene, (26) 2-methylsulfinyl-3-cyano- 4- (4-chlorophenyl) -5-formylthiophene, (27) 2-ethylsulfinyl-3-cyano-6-nitrobenzothiophene, (28) 2-methylsulfinyl-3-cyano-5-formylthlofen, (29) 2-methylsulfinyl-3 -cyan-4-amino-5-ethoxydarbonylthiophene, (30) 2-methylsulfinyl-3-cyano-5-benzoylthiophene, (31) 2-methylsulfinyl-3-cyano-4-chloro-5-benzoylthiophene, (32) 2- phenylsulfinyl-3,5-dicyanothiophene, (33) 2-n-propylsulfinyl-3,5-dicyano-4-chlorothiophene, (34) 2-n-hexylsulfinyl-3,5-dicyano-4-chlorothiophene, (35) 2 -methylsulfinyl-3,5-dicyano-4- (4-chlorophenyl) -thiophene, (36) 2-n-octylsulfinyl-3,5-dicyano-4-chlorothiophene, (37) 2-ethylsulfinyl-3-cyano-4 -chloro-5-ethoxycarbonylthiophene, (38) 2-n-hexylsulfinyl-3,5-dicyano-4-aminothiophene, (39) 2-n-butylsulfinyl-3-cyano-4-chloro-5-acetylth iophene, (40) 2-n-propylsulfinyl-3,5-dicyanothiophene, (41) 2-n-butylsulfinyl-3,5-dicyano-4-methoxythiophene, (42) 2-methylsulfinyl-3-cyano-4-chloro -5- (4-chlorobenzoyl) thiophene, (43) 2-n-butylsulfinyl-3,5-dicyano-4-chlorothiophene, (44) 2-n-butylsulfinyl-3-cyano-5-acetylhthiophene, (45) 2 -phenylsulfonyl-3,5-dicyanothiophene, (46) 2-ethylsulfinyl-3,5-dicyano-4-aminothiophene, (47) 2-ethylsulfinyl-3-cyano-5- (4-chlorobenzoyl) thiophene, (48) 2 -methylsulfinyl-3-cyano-4-amino-5-formylthiophene, (49) 2-ethylsulfinyl-3-cyano-4-amino-5-formylthiophene, (50) 2-ethylsulfinyl-3-cyano-4-chloro-5 -formylthiophene, (51) 2-methylsulfinyl-3-cyano-5-benzoylthiophene, (52) 2-methylsulfinyl-3-cyano-5- (4-chlorobenzoyl) thiophene, (53) -cyan-O-ethylsulfinyl-8- ethylthio-4-chlorostyrene, (54) 2-ethylsulfinyl-3,5-dicyano-4- (N-acetyl-N-methylamino) thiophene, (55) 2-n-propylsulfinyl-3,5-dicyano-4- methoxythiophene, (56) 2-ethylsulfinyl-3-cyano-4-methyl-5-formylthiophene, (57) 2-n-propylsulfinyl-3-cyano-4-amino-5-acetylthiophene, (58) 2-n-butylsulfinyl 3-cyano-4-amino-5-acyl (60) 2-methylsulfinyl-3-cyano-5-methylsulfonylthiophene; (61) 2-n-propylsulfinyl-3-cyan-4; -chloro-5-acetylthiophene, (62) 2-n-propylsulfinyl-3-cyano-4-methyl-5-acetylthiophene, (63) 2-ethylsulfinyl-3,5-dicyano-4-methylthiophene, (64) 2- ethylsulfinyl-3-cyano-5-benzoylthiophene, (65) 2-ethylsulfinyl-3-cyano-4-amino-5-benzoylthiophene, (66) 2-ethylsulfinyl-3-cyano-4-amino-5- (4-chlorobenzoyl) thiophene, (67) 2-n-propylsulfinyl-3-cyano-4-amino-5-benzoylthiophene, (68) 2-ethylsulfinyl-3,5-dicyano-4- (1,2,4-triazole-1- (69) 2-ethylsulfinyl-3,5-dicyano-4- (imidazol-1-yl) thiophene, (70) 2-methylsulfinyl-3,5-diformylthiophene, (71) 2-ethylsulfinyl-3, 5-dicyano-4-phenylthiophene, (72) 2-ethylsulfinyl-3-cyano-4-chloro-5- (4-chlorobenzoyl) thiophene, (73) 2-n-propylsulfinyl-3-cyano-5- (4-) chlorobenzoyl) thiophene, (74) 2-methylsulfinyl-3-cyano-4-methoxy-5-benzoylthiophene, (75) 2-n-propylsulfinyl-3-cyano-4-methoxy-5-benzoylthiophene, (76) 2-ethylsulfinyl 3-Cyano-4-methoxy- 5- (4-chlorobenzoyl) thiophene, (77) 2-ethylsulfinyl-3-cyano-4-chloro-5-methylsulfonylthiophene, (78) 2-benzylsulfinyl-3,5-dicyano-4-chlorothiophene, (79) 2- n-butylsulfinyl-3,5-dicyano-4-bromothiophene, (80) 2-n-butylsulfinyl-3,5-dicyanthiophene, (81) 2-n-octylsulfinyl-3,5-dicyanthiophene, (82) 2-phenylsulfiny1 -3,5-dicyano-4-chlorothiophene, (83) 2-ethylsulfinyl-3,5-diformyl-4-chlorothiophene, (84) 2-ethylsulfonyl-3-cyano-4-chloro-5-methylsulfonylthiophene, (85) 2-methylsulfinyl-3,5-dicyano-4-phenylthiothiophene, (86) 2-n-butylsulfinyl-3-cyano-4-bromo-5-acetylthiophene, (87) 2-ethylsulfinyl-3-cyano-4-phenyl- 5-acetylthiophene, (88) 2-n-butylsulfinyl-3-cyano-4-amino-5-benzoylthiophene, (89) 2-n-butylsulfonyl-3,5-dicyano-4-bromothiophene, (90) 2-n -butylsulfinyl-3-cyano-5-benzoylthiophene, (91) 2-ethylsulfinyl-3-cyano-4-methyl-5-benzoylthiophene, (92) 2-ethylsulfinyl-3-cyano-4-chloro-5-benzoylthiophene, ( 93) E-isomer-cyano-O-methylsulfinyl-O-methylthiostyrene and (94) 2-ethylsulfinyl-3,5-dlcyan-4-phenoxythiophene.

The novel compounds of the present invention show an interesting fungicidal activity on a broad spectrum of pathogenic fungi that can attack agricultural and garden crops.

The compounds of the invention can be used against airborne pathogens, soil diseases and seedborne pathogens. Examples of airborne pathogenic fungi include Uromyces phaseoli and Phytophthora investans.

The novel compounds of the invention have been found to be particularly effective against soil pathogenic microorganisms and seed-borne organisms, i.e., phytopathogenic soil fungi (soil diseases), such as Pythium spp. (for example Pythium ultimum and Pythium splendens) and Rhizoctonia solani (seed potato), against phytopathogenic seed-borne fungi (seed-borne diseases), such as Pyrenophora graminea (brown blotches) on barley, Tilletia caries (Goosefoot) spp. Fusarium nivale and Fusarium culmorum on wheat, Leptosphaeria nodorum on wheat and Ustilago spp. such as Ustilago avenae on oat. Infections with phytophagous fungi, such as seed-borne or soil-borne phytophagous fungi, can be prevented by treating the soil for planting or sowing or, which is usually advantageous for economic reasons, by treating the seed alone with a composition containing the novel compound of the invention.

For practical applications, the compounds of the invention are formulated. In these compositions, the active ingredient is mixed with a solid carrier material or is dissolved or dispersed in a liquid carrier, optionally in combination with excipients such as emulsifiers, wetting agents, dispersing agents and stabilizers.

Examples of compositions of the present invention include aqueous solutions and dispersions, oil solutions and oil dispersions, solutions in organic solvents, pastes, dusts, dispersible powders, miscible oils, granules, pallets, inert emulsions, aerosol formulations and fuming candles.

Dispersible powders and pastes and miscible oils are concentrated formulations which are diluted before or during use.

Solutions in organic solvents are mainly used for aerial application, in which large areas are treated with a relatively small amount of the composition. Solutions of the active ingredients in organic solvents may contain a phytotoxicity reducing agent such as sheep wool fat, fatty acid or sheep wool fat alcohol. In the following, examples of several compositions of the invention are described in detail.

For example, granules are prepared by dissolving the active ingredient in a solvent or dispersing it in a diluent and impregnating a granular carrier material such as porous granules (e.g. sand or crushed saliva) or organic granular materials (e.g. for example, dried coffee grounds, chopped tobacco stems and granulated corn cobs).

The active granular composition can also be prepared by compressing the active ingredient together with the powdered mineral carrier in the presence of lubricants and binders, crushing the compacts and sieving to the desired granule size.

Granular compositions can be further prepared by mixing the powdered active ingredient with a powdered carrier and then agglomerating the mixture to the desired particle size.

The dust may be obtained by intimately mixing the active ingredient with an inert solid carrier material, for example talc.

Dispersible powders are prepared by mixing 10 to 80 parts by weight of a solid inert carrier, for example kaolin, dolomite, gypsum, chalk, bentonite, attapulgite, colloidal silica or mixtures of these and the like, with 10 to 80 parts by weight of active ingredient, 1 to 5% by weight. parts of a dispersant, for example lignin sulphonate or alkyl naphthalene sulphonate, known for use herein, and suitably also with 0.5 to 5 parts by weight of a wetting agent such as a sulphated fatty alcohol, an alkylarylsulphonate, a fatty acid condensation product or a polyoxyethylene derivative and, if necessary ingredients.

For the preparation of miscible oils, the active ingredient may be dissolved in a suitable solvent, preferably poorly miscible with water, and one or more emulsifiers may be added to the solution. Suitable solvents are, for example, xylene, toluene, petroleum distillates rich in aromatics such as solvent naphtha, distilled tar oil and mixtures of these liquids. The emulsifiers which may be used are, for example, polyoxyethylene derivatives and / or alkylarylsulfonates. The concentration of the active ingredient in these miscible oils is not limited by any narrow range and may range, for example, between 2 and 50% by weight. In addition to miscible oils, a liquid and highly concentrated primary composition may be mentioned as a solution of the active ingredient in a liquid which is readily miscible with water, for example in a glycol or glycol ether. To this solution is added a dispersing agent and optionally a surfactant. Dilution of this concentrate with water shortly before or during spraying results in an aqueous dispersion of the active ingredient.

In addition to the aforementioned additives, the compositions of the invention may contain other substances known to be used in compositions of this type.

For example, a glidant such as calcium stearate or magnesium stearate may be added to the dispersible powders and granulation compositions. Adhesives such as polyvinyl alcohol and cellulose derivatives or other colloidal materials such as casein may also be added to improve the adhesion of the pesticide to the treated crop plant. Phytotoxicity-reducing agents of the active compound, carrier material or excipients such as sheep wool fat or sheep wool fatty alcohol may also be added.

Known pesticidal active compounds can also be added to the compositions of the invention. The addition of these substances extends the spectrum of efficacy of the said compositions and may also lead to synergism.

The following known insecticidal, acaricidal and fungicidal compounds are suitable for use in such combination compositions:

Insecticides such as 1) organic chloro derivatives, for example 6,7,8,9,10,10-hexachloro-1,5,5a, 6,9,9a-hexahydro-6,9-methano-2,4,3- benzo (e) dioxathiepine-J-oxide,

2) carbamates such as 2-dimethylamino-5,6-dimethylpyrimidin-4-yl dimethylcarbamate and 2-isopropoxyphenylmethylcarbamate;

3) di (m) ethylphosphates, for example 2-chloro-2-diethylcarbamoyl-1-methylvinyl-, 2-methoxycarbonyl-1-methylvinyl-, 2-chloro-1- (2,4-dichlorophenyl) vinyl- and 2 -chloro-1- (2,4,5-

-trichlorophenyl) vinyl-4-di (m) ethyl phosphate,

4) O, O-di (m) ethyl phosphorothioates, for example O (S) -2-methylthioethyl, S-2-ethylsulfinyl-ethyl, S-2- (1-methylcarbamoylethylthio) ethyl, 0,4-bromo- 2,5-dichlorophenyl, 0-3.5,

6-trichloro-2-pyridyl, 0,2-isopropyl-6-methylpyrimidin-4-yl and 0-4-nitrophenyl-0, 0-di (m) ethylphosphorothioate,

5) O, O-di (m) ethyl phosphorodithioates, e.g., S-methylcarbamoylmethyl, S-2-ethylthioethyl, S- (3,4-dihydro-4-oxobenzo [d] -1,2,3-triazine) -3-ylmethyl) -, S1,2-di (ethoxycarbonyl) ethyl-, S-6-chloro-2-oxobenzoxazolin-3-ylmethyl- and S-2,3-dihydro-5-methoxy-2-oxo-1 3,4-thiadiazol-3-ylmethyl-0,0-di (m) ethylphosphorodithioate

6) phosphonates such as dimethyl 2,2,2-trichloro-1-hydroxyethylphosphonate;

7) benzoylurea derivatives such as N- (2,6-difluorobenzoyl) -N '- (4-chlorophenyl) urea;

8) natural and synthetic pyrethroids,

9) amidines such as N '- (2-methyl-4-chlorophenyl) -N, N-dimethylformamidine; and

10) microbial insecticides such as Bacillus thuringiensis.

Acaricides such as

(1) organotin compounds such as tricyclohexyltin hydroxide and di-tri- (2-methyl-2-phenylpropyl) tin] oxide;

2) organic halogen derivatives such as isopropyl 4,4'-dibromobenzilate, 2,2,2-trichloro-1,1-di (4-chlorophenyl) ethanol and 2,4,5,4'-tetrachlorodiphenylsulfone, and also 3- chloro-ethoxyimino-2,6-dimethoxybenzylbenzoate; and O, O-dimethyl-S-methylcarbamoylmethylphosphorothioate.

Fungicides like

(1) organotin compounds, such as tri-phenyltin hydroxide and triphenyltin acetate;

CS 268823 Β2

(2) alkylene bisdithiocarbamates, for example zinc ethylene bis-dithiocarbamate and manganese ethylene bis-dithiocarbamate;

3) 1-acyl- or 1-carbamoyl-N-benzimidazo-2-ylcarbamates and 1,2-bis (3-alkoxycarbonyl) -2-thioureidobenzene, and

2,4-dinitro-6- (2-octylphenyl crotonate),

1- (bis (dimethylamino) phosphoryl) -3-phenyl-5-amino-1,2,4-triazole,

N-Trichloromethylthiophthalimide

N-tgichloromethylthiotetrahydrophthalimide,

N- (1,1,2,2-tetrachloroethylthlo) tetrahydrophthalimide,

N-dichlorofluoromethylthio-N-phenyl-N, N'-dimethylsulfaride, tetrachloroisophthalonitrile,

2- (4'-thiazolyl) benzimldazole,

5-butyl-2-ethylamino-6-methylpyrimidin-4-yl dimethylsulfamate,

1- (4-chlorophenoxy) -3,3-dimethyl-1- (1,2,4-triazol-1-yl) -2-butanone, 1- [2- (2,4-dichlorophenyl) -4-propyl] -1,3-dioxolan-2-ylmethyl-1H-1,2,4-thiazole,

2,4'-difluoro-cis - (1H-1,2,4-triazol-1-ylmethyl) benzhydryl alcohol,

- (2-chlorophenyl) - N - (4-fluorophenyl) -5-pyrimidinemethanol, d- (2-chlorophenyl) -C 4 - (4-chlorophenyl) -5-pyrimidinemethanol, 1- (isopropylcarbamoyl) -3- (3,5-dichlorophenyl) hydantoin,

N- (1,1,2,2-tetrachloroethylthio) -4-cyclohexene-1,2-carboximide,

N-trichloromethylthio-4-cyclohexene-1,2-dicarboximide,

N-tridecyl-2,6-diinethylmorpholine a

5,6-dihydro-2-methyl-1,4-oxathiine-3-carboxanilide.

The dosage of the compositions according to the invention in practice will, of course, depend on various factors, for example the area to be treated, the active ingredient selected, the form of the composition, the nature and extent of the infestation and the weather conditions.

In general, favorable results are obtained with dosages corresponding to 250 to

1000 g of active substance per hectare.

Application against phytophagous co-organisms gives good results when the soil is treated with a composition containing the active compound according to the invention in an amount corresponding to the application of 2 to 100 kg of active compound per hectare.

When applied to the seed alone, the active ingredient is preferably applied in an amount of 100 to 1500 mg / kg of seed.

The novel thio compounds of the present invention can be prepared, for example, by treating a compound of formula IX

? 1 X 1 R WITH 1 z - c = c - c = C-Y

in which

R, R p R ₂ , X, Y, and Z are as defined above, (IX)

CS 26-823 B2 reacts with an oxidizing agent.

Suitable oxidizing agents are hydrogen peroxide and peroxycarbonyl acids, for example permenic acid, peracetic acid or substituted perbenzoic acids, such as p-nitroperbenzoic acid or m-chloroperbenzoic acid.

Hydrogen peroxide is preferably used as the oxidizing agent to prepare the corresponding sulfones. When using peroxycarboxylic acids, for example the peroxycarboxylic acids mentioned above, the sulfide can be selectively oxidized to the sulfoxide. These oxidation reactions are preferably carried out in a polar organic solvent, for example formic acid, acetic acid, a ketone such as acetone, or a chlorinated hydrocarbon such as methylene chloride. The reaction temperature depends on the reactants used and the reaction solvent, and may be between -20 ° C and the boiling point of the solvent, preferably between -10 ° C and room temperature.

The final product can be optionally purified by recrystallization or column chromatography after isolation.

The thiophenes used for the oxidation reaction described above can be prepared as described below.

Thiophenes of formula VI

f * CN rX (VI) R

in which

R and R are as defined above, and? 5 ^and? 5 are identical or different and are hydrogen, alkyl having 1 to 4 carbon atoms or alkylcarbonyl group having 2 to 5 carbon atoms is prepared by reacting a compound of formula VII

(VII) with a base, whereupon the amino group in the resulting compound of formula (VI) in which R @ 1 is hydrogen may be optionally converted by treatment with an appropriate acylating and / or alkylating agent to the corresponding acylated or alkylated amino group.

A suitable base for the cyclization reaction is an alkali metal hydride or an alkali metal hydroxide such as sodium hydride, sodium hydroxide or potassium hydroxide. This reaction does

CS 268823 82 is preferably carried out in a dipolar aprotic solvent, for example dimethylformamide, at a temperature between 0 ° C and the boiling point of the solvent. As the alkylating agent, a suitable halide or dialkyl sulphate may be used, preferably in the same solvent, preferably at a slightly lower temperature.

A suitable acyl halide or acid anhydride may be used as the acylating agent, preferably in the presence of a suitable catalyst, such as an organic base, preferably 4- (N, N-dimethylamino) pyridine.

The starting compound (VII) can be prepared according to the following reaction scheme:

RHal RS. CN / (CH3Hal) - Hal ** -OF CN - Hal '

(VII)

The product of formula (VII), like the other intermediates in square brackets, is usually not isolated but is immediately converted to the desired thiophene of formula (VI) by treatment with a base.

In the above reaction scheme, Hal is a halogen atom such as chlorine. The first reaction step is preferably carried out in a polar solvent, for example a dipolar aprotic solvent such as dimethylformamide, at a reduced temperature. The second reaction step is carried out under the same reaction conditions using a suitable alkylating agent,

For example, the corresponding halide or dialkyl sulfate. The third reaction step is preferably carried out in the same solvent at a temperature comprised between 0 ° C and the boiling point of the solvent.

Compounds of formula VI in which a is hydrogen may alternatively be prepared via the following intermediates:

The thus obtained 4-aminothiophenes can be converted to thiophenes unsubstituted in the 4-position by reaction with an alkyl nitrite, preferably in a polar organic solvent, for example a dipolar aprotic solvent such as dimethylformamide, preferably at elevated temperature, e.g. C. As the alkyl nitrite, for example, isoamyl nitrite can be used.

The aforementioned 4-aminothiophenes can be converted to the corresponding 4-halothiophenes by reaction with an alkyl nitrite or an alkali metal nitrite, for example sodium or potassium nitrite, in the presence of the desired halide ions, e.g.

The reaction with the alkali metal nitrite is preferably carried out in a polar organic solvent, for example methylene chloride or acetonitrile, optionally in a two-phase system containing water or saturated sodium chloride solution. The conversion can be aided by the addition of a catalyst, for example a metal halide such as copper (I) chloride. The reaction with sodium nitrite in the presence of anhydrous metal halide is preferably carried out in a polar organic solvent such as acetonitrile.

Thiophenes corresponding to the general formula

WITH

CS 268023 B2 in which

R and Rj are as defined above and

R ₆ represents a C 1 -C 4 alkyl group, which may be prepared by reacting a compound of formula

with a suitable alkylating agent, for example an alkyl halide. This reaction is preferably carried out in a polar organic solvent, for example acetonitrile, at a temperature between 0 ° C and the boiling point of the solvent, using a suitable base, for example potassium carbonate, and in the presence of a suitable amine such as triethylamine. ‘

The 4-hydroxythiophene used as the starting material in the latter reaction can be obtained according to the following reaction scheme:

Thiophenes of general formula

in which

R and Rj are as defined above and

R ₀ represents a C 1 -C 4 alkyl group or an optionally substituted phenyl group, which may be prepared by reacting a compound of formula VIII

(VIII) sequentially with a compound of formula

_T R - CH ₂ -Hal and with a compound of the formula *

R-rlal where _t

Hal represents a halogen atom.

These reactions are preferably carried out in a polar organic solvent, for example dimethylformamide, at a temperature between 0 ° C and the boiling point of the solvent.

The starting materials of formula (VIII) may be prepared by reacting carbon disulphide and a base with a compound of formula (I)

R® - C - _CH2 - CN

This reaction is preferably carried out in the same solvents as above and at a slightly reduced temperature.

CS 26-823 B2

Thiophenes of general formula ^R 2k * 1 7 Ar

in which

R 2 ^and R 2 are as defined above and

Ar represents an optionally substituted phenyl group.

is best prepared by reacting the thiophene of the general formula

Wherein each individual symbol is as defined above, with a thiophsol of the general formula

ArSH

This reaction is preferably carried out in a polar organic solvent, for example acetonitrile, at a temperature between 0 ° C and the boiling point of the solvent. If desired, the conversion can be facilitated by the use of an organic base, for example an amine, such as triethylamine.

Intermediate 3,5-diformylthiophenes can be prepared from the corresponding 3,5-dicyanthiophenes by the procedure described in J. Org. Chem. 29, 3046-3049 (1964).

Intermediate 5-alkylsulfonylthiophenes can be prepared from the corresponding 5-alkoxycarbonylthiophenes by the following sequence of reactions:

The ester group at the 5-position is saponified to give the free carboxylic acid, which is decarboxylated, for example by treatment with a copper powder and an amine such as quinoline, chlorosulfonation is performed, e.g. with chlorosulfonic acid in the presence of phosphorus to the corresponding alkali metal sulfinate by treatment with an alkali metal sulfite and a base, followed by alkylation, for example with an alkyl halide.

Intermediate 4-phenoxy- or 4-phenylthiothiophenes can be prepared by reacting the corresponding 4-halo-thiophenes with an optionally substituted phenol or a phenol. thiophenol. Accordingly, thiophenes substituted with an amino group forming part of the heterocyclic ring can be prepared by reacting the corresponding 4-halo-thiophene with a heterocyclic amino modality.

1 $

Intermediate compounds of general formula

wherein the individual symbols are as defined above, may be prepared by reacting a compound of the formula

CN with carbon disulfide and a suitable base such as an alkali metal hydride such as sodium hydride, preferably in a polar organic solvent such as dimethylformamide at a slightly elevated temperature and then alkylating the resulting compound with a suitable alkylating agent such as an alkyl halide of the formula

R ₆ -Hal

Intermediate benzothiophenes of general formula

in which

R @ 1 and R @ 2 are as defined above, and can be prepared according to the following reaction scheme:

Hal

2e ~

base

---------->

- Hal p

Or R ₂ ^SO 4

-------------- ^- ►

-Hal or -S0 ² ~

The first reaction step may be carried out by reacting the starting material in which Hal is a halogen atom with carbon disulfide in the presence of a suitable base, for example sodium hydride, preferably in a polar organic solvent, for example dimethylformamide, at a temperature between 0 ° C and the boiling point of the solvent. The following reactions can then be carried out in the same manner as the corresponding reactions described above.

The invention is illustrated by the following non-limiting examples.

Example 1

Preparation of 2-methylsulfinyl-3-cyano-5-acetylthiophene (Compound No. 1)

To a solution of 5.0 g of 2-methylthio-3-cyano-5-acetylthiophene in 500 ml of methylene chloride was added 5.0 g of 83% m-chloroperbenzoic acid while stirring at 0-5 ° C. After stirring for 30 minutes at 5 ° C, about 50 mL of saturated aqueous sodium bicarbonate solution was added and the reaction mixture was stirred for 60 minutes. The organic layer was separated and dried after washing with water. After distilling off the solvent, the desired product is obtained in a yield of 4.6 g.

In an analogous manner, optionally using p-nitroperbenzoic acid such as

CS 268623 B2 oxidizing agent and chloroform as solvent, prepare the following compounds #

compound number melting point (° C); thin layer chromatography

2 153 3 148 4 145 5 94 6 186 - .188 7 130 8 80 3 • 109 10 166 11 192-195 12 130 13 100 ALIGN! 14 98 15 Dec syrup; (dichloromethane) = 17 130 19 Dec syrup; Rf (dichloromethane) 20 May 115-118 23 74 24 94 (decomposition) 25 120 26 171-173 27 Mar: 156-158 28 112-115 29 167-169 30 127.5 - 133.5 31 91-97 32 90 - 93 33 104 - 105.5 34 58 35 169-171 36 oil; _Rf (dichloromethane) = 0 37 77 - 79 38 119 39 70-71 40 72-74 41 70 42 123–127 43 78 - 79 44 80-81 46 143-146 47 103-106 48 170-172 49 137-139 50 62-87 51 124-128 52 136.5 - 138 53 oil; Rf (diethyl ether) = 0 54 syrup; Rf (dichloromethane) = i

CS 268823 82

compound number melting point (° C) ₅ thin layer chromatography 55 83 56 76-78 , 57 155-157 58 143-145 59 120 60 146-151 61 114-116 62 46 - 48 63 93-95 64 86-88 65 164-167 66 174-177 67 124–127 68 . 127-128 69 125-128 70 140-142 71 124–126 72 109-111 73 82-86 74 79-84 75 69-72 76 151 (decomposition) 77 172-174 78 149-151 79 113-115 80 oil; R * (dichloromethane) 81 oil; Rf (dichloromethane) 82 132-135 83 90-92 85 99-101 86 84-86 87 117-119 88 90-92 90 oil; R _f (dichloromethane) 91 68-73 92 110 93 84-87 94 94-96

0.18

0.15

0.14

CS 268823 82

Example 2

Preparation of 2-ethylsulfonyl-3,5-dicyanthiophene (Compound No. 16)

To a solution of 1.62 g of 2-ethylthio-3,5-dicyanthiophene in 50 ml of acetic acid, 2 ml of 35 X hydrogen peroxide are added, the mixture is heated to about 100 ° C for about 1 hour, and another milliliter of 35 X is added. hydrogen peroxide and heating to about 100 ° C was continued for an additional hour. The product crystallized upon cooling of the reaction mixture is filtered off with suction and washed with ethanol. 1.49 g of the desired compound of melting point 121 DEG-124 DEG C. is obtained.

The following compounds were prepared accordingly:

compound number melting point (° C)

18 138 - 140 21 115 - 117 22nd 140 - 143 45 189 - 191 84 216 - 218 89 119 - 121

Example 3

Preparation of 2-methylthlo-3,5-dicyano-4-aminothiophene

To a solution of 26.5 g of malonic acid dinitrile in about 250 ml of dimethylformamide, to which 45 ml of carbon disulfide was added, a concentrated solution of 50 g of potassium hydroxide in about 30 ml of water was slowly added dropwise. During the addition, the mixture was stirred and kept at a temperature of 0 to 10 ° C by cooling. After 10 minutes, 60.0 g of methyl iodide was slowly added dropwise with stirring and cooling, and after another 30 minutes, 30.5 g of chloroacetonitrile was added dropwise. The cooling bath was removed and 4.0 g of powdered potassium hydroxide was added to the reaction mixture at a temperature of about 42 ° C. After stirring for an hour at 30-35 ° C, 600 ml of water and 100 ml of diethyl ether are added, the precipitate formed is filtered off with suction, washed successively with water, isopropyl alcohol and diethyl ether, and dried. The desired product sublimating at 260 ° C was obtained in a yield of 54.5 g.

_t In a corresponding manner the following compounds:

2-ethylthio-3-cyano-4-amino-5-acetylthifene used for the preparation of compound 10 according to Example 1,

2-methylthio-3-cyano-4-amino-5-ethoxycarbonylthiophene used for the preparation of compound 29 according to Example 1,

2-n-hexylthio-3,5-dicyano-4-aminothiophene used for the preparation of compound 38 according to example 1,

2-ethylthio-3,5-dicyano-4-aminothiophene used for the preparation of Compound No. 46 according to Example 1,

2-methylthio-3-cyano-4-amino-5-formylthiophene used for the preparation of compound 48 according to example 1,

2-ethylthio-3-cyano-4-amino-5-formylthiophene used to prepare Compound No. 49 of Example 1;

2-n-propylthio-3-cyano-4-amino-5-acetylthiophene used to prepare Compound No. 57 according to Example 1,

CS 268823 82

2-n-butylthio-3-cyano-4-amino-5-acetylthiophene used to prepare Compound No. 58 according to Example 1,

2-ethylthio-3-cyano-4-amino-5-benzoylthiophene used to prepare Compound No. 65 according to Example 1,

2-ethylthio-3-cyano-4-amino-5- (4-chlorobenzoyl) thiophene used to prepare Compound No. 66 according to Example 1,

2-n-propylthio-3-cyano-4-amino-5-benzoylthiophene used for the preparation of Compound No. 67 according to Example 1 »

2-n-butylthio-3-cyano-4-amino-5-benzoylthiophene used for the preparation of the compound No. 88 according to example 1 and further

2-methylthio-3-cyano-4-amino-5-acetylthiophene,

2-ethylthio-3,5-dicyano-4-aminothiophene,

2-ethylthio-3-cyano-4-amino-5-formylthiophene, 2-n-propylthio-3,5-dicyano-4-aminothiophene, 2-methylthio-3-cyano-4-amino-5-formylthiophene, 2- methylthio-3-cyano-4-amino-5-benzoylthiophene, 2-n-octylthio-3,5-dicyano-4-aminothiophene,. .

2-ethylthio-3-cyano-4-amino-5-ethoxycarbonylthiophene, 2-methylthio-3-cyano-4-amino-5- (4-chlorobenzoyl) thiophene,

2-n-Butylthio-3,5-dicyano-4-aminothiophene

2-n-propylthio-3-cyano-4-amino-5- (4-chlorobenzoyl) thiophene; and 2-benzylthio-3,5-dicyano-4-aminothiophene.

Example 4

(a) Thiophenes unsubstituted at position 4, used for the preparation of compounds 1, 4, 8, 9, 16, 21, 28, 30, 40, 44, 47, 51, 52, 64, 73, 80, 81 and 90 Examples 1 and 2 were prepared by the following procedure from the corresponding 4-aminothiophenes obtained according to Example 3.

Preparation of 2-methylthio-3,5-dicyanthiophene

20.0 g of 2-methylthio-3,5-dlcyan-4-aminothiophene, prepared as described in Example 3, was added portionwise to a solution of 20.0 g of isoamylnitrite in 300 ml of dimethylformamide, stirred in portions at 62 ° C. The reaction mixture was stirred at 65-70 ° C for a further 30 minutes and then evaporated to a volume of 100 ml. 400 ml of water are added to the residue, the precipitate is filtered off with suction, washed successively with water, isopropanol and petroleum ether, taken up in about 300 ml of methylene chloride, dried, filtered over silica gel and decolourised with charcoal. After addition of isopropanol, methylene chloride is evaporated, the crystalline product is filtered off with suction, washed successively with isopropanol and petroleum ether and dried. Yield 14.0 g of the title compound, m.p. 117 ° C.

b) 4-halo-thiophenes used for the preparation of compounds No. 2, 3, 5, 7, 18, 22, 31, 33, 34, 36, 37, 39, 42, 43, 50, 61, 72, 78, 79, 86 89 and 92 of Examples 1 and 2 were prepared from the corresponding compounds prepared according to Example 3 as follows.

Preparation of 2-ethylthio-3,5-dicyano-4-chlorothiophene

Dissolve 100 g of copper chloride dihydrate in 300 ml of concentrated hydrochloric acid, add 2 liters of acetonitrile to the solution and, concurrently with cooling to -5 ° C, add in portions a concentrated aqueous solution of 60 g of sodium nitrite and 121,2 g of 2- Ethylthio-3,5-dicyano-4-aminothiophene prepared according to Example 3. The cooling was discontinued, the mixture was stirred for a further 1 hour, then the precipitate formed was filtered off with suction and washed with acetonitrile. The filtrate is evaporated, the residue is dissolved in methylene chloride, the solution is washed with water, dried and, after filtration, evaporated. The desired 2-ethylthio-3,5-dicyano-4-chlorothiophene can be purified by dissolving it in methylene chloride and subjecting it to silica gel chromatography. The product can be recrystallized by evaporating methylene chloride from the eluate and adding diisopropyl ether to the residue. The yield of the desired product melting at 93-96 ° C is 52.66 g.

Alternatively, 4-halo-thiophenes can be prepared as follows.

Preparation of 2-n-butylthio-3-cyano-4-chloro-5-benzoylthiophene

To 10.1 g of anhydrous cupric chloride in 100 ml of dry acetonitrile, 15 ml of isoamyl nitrite is added while maintaining the temperature between 65 and 70 ° C, and a solution of 15.8 g of 2-n is added while stirring and maintaining the temperature at about 65 ° C. butylthio-3-cyano-4-amino-5-benzoylthiophene, prepared according to Example 3, in 200 ml of dry acetonitrile. After stirring at 65-70 ° C for half an hour, the reaction mixture was cooled to room temperature and evaporated. The residue was dissolved in methylene chloride, 6N hydrochloric acid was added to the solution, the methylene chloride layer was separated, washed with 6N hydrochloric acid, dried and, after filtration and addition of isopropanol, partially evaporated. The desired 2-n-butylthio-3-cyano-4-chloro-5-benzoylthiophene crystallizes, which is filtered off with suction and dried. The yield of the product melting at 78-80 ° C is 11.85 g.

c) 2-Ethylthio-3-cyano-4-N-methylamino-5-acetylthiophene used to prepare Compound No. 17 of Example 1 was prepared from the corresponding 4-aminothiophene obtained by the procedure of Example 3.

To a solution of 5.4 g of 2-ethylthio-3-cyano-4-amino-5-acetylthiophene in 100 ml of dimethyl sulfoxide was added portionwise with stirring, 1.2 g of 55% sodium hydride. The mixture was stirred for 45 minutes and 2.5 mL of dimethyl sulfate was added slowly. After stirring for an additional hour, the mixture is poured into 400 ml of water, the precipitate formed is filtered off and washed successively with water, petroleum ether, a small amount of isopropanol and again with petroleum ether. Recrystallization from isopropanol gave 2.73 g (2.73 g) of 2-ethylthio-3-cyano-4-N-methylamino-5-acetylthiophene.

d) 2-Ethylthi-3,5-dicyano-4- (N-acetyl-N-methylamino) thiophene used for the preparation of Compound No. 54 according to Example 1 was prepared from the corresponding 4-aminothifene obtained according to Example 3.

To a suspension of 21 g of 2-ethylthi-3,5-dicyano-4-aminothiophene, 3 g of 4- (N, N-dimethylamino) pyridine and 20 ml of triethylamine in 300 ml of acetonitrile, 18 g of acetic anhydride are added dropwise with stirring at 50 ° C. . After evaporation, the residue is taken up in diethyl ether containing 5% acetic acid, the precipitate formed is filtered off with suction, washed successively with water, isopropanol, diethyl ether, toluene and again with diethyl ether and dried. 16 g of the corresponding 4-N-acetylamino compound are obtained.

20 g of methyl iodide are added to a mixture of 16 g of this compound and 12 g of potassium carbonate in 300 ml of acetonitrile. The reaction mixture is stirred and refluxed for 5 hours, during which time 3 portions of about 12 g of methyl iodide are added. The liquid was removed by decantation and the solid material was washed successively with acetonitrile and methylene chloride. The liquid was combined with the filtrate, evaporated to dryness and the residue taken up in methylene chloride. After addition of isopropanol, decolourisation with activated carbon and evaporation of the methylene chloride, 2-ethylthio-3,5-dicyano-4- (N-acetyl-N-methylamino) thiophene is obtained in a yield of 9 g.

Example 5

The 2-methylthio-3,5-diformylthiophene used for the preparation of Compound No. 70 of Example 1 was prepared as follows.

To a suspension of 7.20 g of 2-methylthio-3,5-dicyanthiophene obtained by the procedure of Example 4a) in 120 ml of dry toluene, 75 ml of a 20% solution of diisobutylaluminum hydride in toluene are added under stirring under nitrogen. The reaction mixture was stirred for 2 hours and then 12 ml of methanol was added under ice-cooling. Concentrated sulfuric acid was added to the resulting mixture while cooling in ice and stirring until clear. The toluene phase is separated and the aqueous phase is washed twice with toluene. The combined organic phases were washed with water, dried and evaporated after filtration. The residue was recrystallized from ethanol to give 3.0 g of 2-methylthio-3,5-diformylthiophene, m.p. 135-137 ° C.

Correspondingly, 2-ethylthio-3,5-diformyl-4-chlorothiophene used for the preparation of Compound No. 83 of Example 1 was obtained from 2-ethylthio-3,5-dicyano-4-chlorothiophene prepared as described in Example 4b).

Example 6 (a) Preparation of 2-methylthio-3,5-dicyano-4-hydroxythiophene

To a solution of 20.0 g of cyanoacetic acid methyl ester and 18.0 g of carbon disulfide in about 300 ml of dimethylformamide, a cold, very concentrated solution of 25 g of potassium hydroxide in about 15 ml of water is slowly added dropwise with stirring and cooling below 0 ° C. After stirring for 20 minutes, a solution of 15.5 g of chloroacetonitrile in 10 ml of acetonitrile is added dropwise to the mixture at a temperature of -5 ° C to 0 ° C, and the resulting mixture is stirred for a further 30 minutes. and stirring was continued for another 30 minutes at 40 ° C. To the mixture is first added 29 g of methyl iodide and after 30 minutes 25 ml of concentrated hydrochloric acid, the reaction mixture is concentrated under reduced pressure to a volume of about 300 ml and about 600 ml of water are added to the residue. The precipitate formed is filtered off with suction, washed successively with water, a small amount of isopropanol and diisopropyl ether, and dried. Yield 19.0 g to give the desired product of melting point above 200 ° C ^G

The following compounds were prepared accordingly:

2-ethylthio-3,5-dicyano-4-hydroxythiophene, 2-ethylthio-3-cyano-4-hydroxy-5-acetylthiophene, 2-propargylthio-3,5-dicyano-4-hydroxythiophene, 2-ethylthio 3-cyano-4-hydroxy-5-acetylthiophene, 2-n-butylthio-3,5-dicyano-4-hydroxythiophene, 2-n-propylthio-3,5-dicyano-4-hydroxythiophene, 2- »ethylthio- 3-cyano-4-hydroxy-5-benzoylthiophene, 2-n-propylthio-3-cyano-4-hydroxy-5-benzoylthiophene and 2-ethylthio-3-cyano-4-hydroxy-5- (4-chlorobenzoyl) thiophene .

(b) From the compounds obtained according to Example 6 (a), the 4-alkoxythiophenes used to prepare compounds Nos. 12, 13, 14, 23, 24, 25, 41, 55, 59, 74, 75, and 76 of Example 1 were prepared as follows. 1.

Preparation of 2-methylthio-3,5-dicyano-4-methoxythiophene

A mixture of 6 g of 2-methylthio-3,5-dicyano-4-hydroxythiophene, 10 ml of methyl iodide, 10 g of potassium carbonate and 3 ml of triethylamine is heated under reflux in 30D ml of acetonitrile with stirring for 2 hours. and the filtrate was evaporated to dryness. The residue is taken up in 200 ml of methylene chloride and the organic solution is washed successively with aqueous potassium carbonate solution and water. The methylene chloride solution was dried and evaporated to dryness. The residue was recrystallized from isopropanol to give 4.0 g of the desired product, m.p. 132 ° C.

Example 7

Preparation of 2-ethylthio-3-cyano-4-methyl-5-acylthiophene

To a suspension of 10.5 g of cyanacetone sodium in 200 ml of dimethylformamide, 9.0 ml of carbon disulfide are added successively, under stirring and cooling in ice,

CS 268823 82

4.5 g of sodium hydride dispersion. After stirring for 1 hour with cooling, 8.4 ml of chloroacetone was added dropwise under the same reaction conditions. After stirring for an additional hour, 0.4 g of powdered sodium hydroxide was added, and the resulting mixture was stirred for a further 0.5 hours, then 8.0 ml of ethyl iodide were added under the same conditions. The reaction mixture was stirred for 1 hour then allowed to stand overnight, poured into 1 liter of ice-water and extracted with diethyl ether. The organic phase is washed three times with water, dried, clarified with charcoal and evaporated after filtration. The residue is recrystallized from isopropanol to give 9.54 g of the desired product, m.p. 51-52 ° C.

In a similar manner, additional 4-alkylsubstituted thiophenes were used as starting materials for the preparation of Compounds Nos 56, 62, 63 and 91 of Example 1.

2-Methylthio-3-cyano-4- (4-chlorophenyl) -5-acetylthiophene, which is the starting material for the preparation of Compound 6 according to Example 1, is obtained accordingly, using as solvent in the first reaction step instead of dimethylformamide, dimethylsulfoxide.

Additional 4-aryl-substituted thiophenes were prepared in an analogous manner as starting materials for the preparation of Compounds Nos. 26, 35, 71 and 87 of Example 1.

Example 8

The following describes the preparation of 2-ethylthio-3-cyano-6-chlorobenzothiophene, which is the starting material for the preparation of compound 20 of Example 1.

To a solution of 7.44 g of 2,4-dichlorophenylacetonitrile in 80 ml of dry dimethylformamide was added, under stirring and cooling in cold water, 3.62 ml of carbon disulfide and then gradually 3.6 g of sodium hydride dispersion. After stirring for one hour, ethyl iodide (3.20 ml) was added dropwise under the same conditions. The reaction mixture was stirred first at room temperature for 1 hour and then at 100 ° C for 24 hours, then cooled and poured into ice water. The precipitate formed is filtered off with suction, washed with water and petroleum ether and recrystallized from ethanol. Yield 3.89 g of the desired product, m.p. 91-93 ° C.

The following compounds were prepared accordingly:

2-methylthio-3-cyano-4-chlorobenzothiophene used as starting material for the preparation of Compound No. 11 of Example 1; and

2-ethylthio-3-cyano-6-nitrobenzothiophene used as starting material for the preparation of Compound No. 27 of Example 1.

Example 9

The procedure described by Chauhan et al. in Tetrahedron 1976, 32 (14), p. 1779, -cyan-0,0-bls (methylthio) -3,4-dichlorostyrene, used as starting material for the preparation of Compound No. 15 of Example 1, was prepared. cyano-0,0-bis (methylthio) -4-chlorostyrene, used as starting material for the preparation of compounds No. 19 of Example 1, as well as starting materials for the preparation of compounds No. 53 and 93 of Example 1.

Example 10

Preparation of 2-phenylthio-3,5-dicyanthiophene used as starting material for the preparation of Compound No. 32 of Example 1 and Compound No. 45 of Example 2.

To a solution of 8.9 g of 2-ethylsulfinyl-3,5-dicyanthiophene obtained in Example 1 in 100 ml of acetonitrile, 4.4 ml of thiophenol and 5.0 ml of triethylamine are added under stirring. The reaction mixture was allowed to stand overnight and then heated to reflux for 8 hours. The solvent was evaporated, the residue was taken up in methylene chloride and chromatographed on a dry silica gel column (1 liter column volume). The desired product, m.p.

CS 266823 B2

? -71 DEG C. is obtained in a yield of 9.07 g. Any 2-alkylsulfinyl compound may optionally be used as starting material.

Accordingly, 2-phenylthio-3,5-dicyano-4-chlorothiophene used as starting material for the preparation of Compound No. 82 of Example 1 was also prepared.

Example 11

Preparation of 2-methylthio-3-cyano-5-methylsulfonylthiophene used as starting material for the preparation of Compound No. 60 according to Example 1.

To a solution of 4.36 g of 2-methylthio-3-cyano-5-ethoxycarbonylthiophene obtained as described in Example 4 (a) in 40 ml of dioxane was added 40 ml of 2N sodium hydroxide with stirring. After stirring for 2 hours, the reaction mixture is acidified with 45 ml of 2N hydrochloric acid, the precipitated 5-carboxythiophene derivative is filtered off with suction, washed with water and recrystallized from acetonitrile. 3.01 g of the expected product are obtained, m.p. 230-234 ° C.

1.99 g of this 5-carboxythiophene derivative are heated to 200 ° C with about 4 ml of quinoline and 0.4 g of copper powder for about 15 minutes. After cooling, diethyl ether, water and 20 ml of 2N hydrochloric acid were added to the reaction mixture, the ether phase was separated, washed with water, dried, clarified with charcoal and evaporated after filtration. Yield of oily 2-methylthio-3-cyanthiophene o (dichloromethane) = 0.45. This reaction was repeated using larger amounts of starting materials.

6.96 g of the product obtained are added dropwise to a mixture of 7.1 ml of chlorosulfonic acid and 8.9 g of phosphorus pentachloride while stirring and cooling to below 20 ° C. The reaction mixture was stirred at room temperature for 0.5 h and then poured onto ice. The precipitate formed is filtered off with suction, washed with water and dissolved in methylene chloride. The solution was dried, decolourised with charcoal, filtered, diisopropyl ether was added to the filtrate and the methylene chloride was evaporated. The desired 2-methylthio-3-cyano-5-chlorosulfonylthiophene precipitates in a yield of 7.60 g, m.p. 112-115 ° C.

The chlorosulfonyl derivative obtained above is converted to the corresponding methylsulfonyl derivative via the corresponding sodium sulfinate. The reaction is carried out by adding 7.50 g of the chlorosulfonyl derivative to 7.60 g of sodium sulfite and 10.1 g of sodium bicarbonate in 60 ml of water, while slowly stirring the reaction mixture to 70 ° C and 70 ° C. is stirred for 0.5 hour. 3.75 ml of methyl iodide was added to the resulting solution, and the mixture was heated under reflux for 5 hours, after which time the volatiles were evaporated in vacuo. The precipitate formed is filtered off with suction, washed with water and recrystallized from methanol. Yield: 2.88 g, 2-methylthio-3-cyano-5-methylsulfonylthiophene, m.p. 126 DEG-128 DEG.

In a similar manner, 2-ethylthio-3-cyano-4-chloro-5-methylsulfonylthiophene used as the starting material for the preparation of Compound No. 77 of Example 1 and Compound No. 64 of Example 2 was prepared.

Example 12

Preparation of 2-ethylthio-3,5-dicyano-4-phenoxythiophene used as starting material for the preparation of Compound No. 94 according to Example 1.

2.32 g of phenol are dissolved in 30 ml of methanol containing 0.69 g of sodium. After addition of 50 ml of dimethylformamide, the methanol is evaporated and the remaining solution is added with stirring to a solution of 6.86 g of 2-ethylthio-3,5-dicyano-4-chlorothiophene obtained in Example 4 (b) in 40 ml of dimethylformamide. After stirring for 1 hour, the reaction mixture is poured into 0.5 L of ice-water, the precipitate formed is filtered off with suction, washed with water and dissolved in methylene chloride. The solution was washed with brine, dried, filtered and partially evaporated after addition of diisopropyl ether. The crystallized product is filtered off with suction to give 5.78 g of 2-ethylthio-3,5-dicyano-4-phenoxythiophene, m.p. 111-112 ° C.

CS 268823 82

In a similar manner, 2-methylthio-3,5-dicyano-4-phenylthiophene was used as a starting material for the preparation of Compound No. 85 according to Example 1.

Example 13

Preparation of 2-ethylthio-3,5-dicyano-4- (1,2,4-triazol-1-yl) thiophene, which is used as starting material for the preparation of Compound No. 68 according to Example 1.

0.69 g of sodium is dissolved in 30 ml of methanol, 30 ml of dimethylformamide are added to the solution, the methanol is evaporated and 2.07 g of 1,2,4-triazole in 30 ml of dimethylformamide are added to the residue. The mixture is heated to reflux with stirring under nitrogen for 1.5 hours, then cooled in an ice / acetone mixture, and a solution of 6.86 g of 2-ethylthio-3,5-dicyano-4-chlorothlophene is added, obtained in the procedure of Example 4 (b) in 40 ml of DMF, the reaction mixture was stirred overnight and then poured into 0.5 L of ice-water. The precipitate formed is filtered off with suction, washed with water and dissolved in methylene chloride. The organic phase is dried, decolourised with activated carbon, filtered, partially evaporated and diisopropyl ether is added to the residue. The precipitated desired 2-ethylthio-3,5-dicyano-4- (1,2,4-triazol-1-yl) thiophene is filtered off with suction, washed with diisopropyl ether and dried. 4.30 g of product are obtained, m.p. 148-151 ° C.

Accordingly, 2-ethylthio-3,5-dicyano-4- (imidazol-1-yl) thiophene was prepared as a starting material for the preparation of Compound No. 69 according to Example 1.

EXAMPLE 14 (a) Preparation of a solution of the active ingredient, ie 2-methylsulfinyl-3-cyano-5-acetylthiophene (# 1) in a water-miscible liquid (liquid preparation).

g of the above active substance is dissolved in 10 ml of isophorone and about 70 ml of dimethylformamide and 10 g of polyoxyethylene glycol ricinil ether are added as emulsifier.

In an analogous manner, other active substances according to the invention can also be processed to such liquid preparations with an active compound concentration of 10% or 20%.

Similarly, liquid preparations can be prepared using N-methylpyrrolidone, dimethylformamide and mixtures of N-methylpyrrolidone and isophorone as solvents.

(b) Preparation of a solution of the active ingredient in an organic solvent.

Dissolve 200 mg of the active substance in 1000 ml of acetone containing 1.6 g of polyoxyethylene nonylphenol. After pouring into water, the resulting solution can be used as a spray liquid.

(c) Preparation of an emulsifiable concentrate containing the active ingredient.

g of the active substance is dissolved in a mixture of 15 ml of isophorone and 70 ml of xylene and 5 g of a mixture of sorbitan polyoxyethylene ester and alkylbenzene sulphonate are added as emulsifiers.

(d) Preparation of a dispersible powder (wettable powder) containing the active ingredient.

68 g of kaolin are mixed in the presence of 2 g of sodium butylnaphthalenesulfonate and 5 g of lignin sulfonate.

(e) Preparation of a suspension concentrate containing the active ingredient.

A mixture of 10 g of active ingredient, 2 g of lignin sulphonate and 0.8 g of sodium alkyl sulphate is made up to 100 ml with water.

(f) Preparation of a granulate containing the active ingredient.

CS 268823 82

7.5 g of the active ingredient, 5 g of sulphite waste liquors and 87.5 g of ground doltomite are mixed and processed in a manner known per se into a granular composition.

Example 15

Seed pickling test to protect germinal plants against Fusarium culmorum phytopathogenic fungus.

Wheat seed infected with Fusarium culmorum, is treated with the active substance to be tested, adjusted to a suitable formulation, at a dose of 3 g per kilogram of seed. A suitable formulation is obtained by grinding the test compound to a powder and mixing it thoroughly with kaolin at a concentration of 10% by weight. The treated seed is sewn with flat dishes filled with soil, which are then placed in an air-conditioned chamber where the temperature is maintained at 8-12 ° C. After 3 weeks the number of emerged and healthy plants is determined. As a control, emergence of healthy plants from untreated seed. The following known substances are also tested for comparative purposes:

(a) 2-methylsulfinyl-4-methyl-5-nitrothiazole, (b) 2-methylsulfinyl-3-nitrothiophene, and (c) 2-ethylsulfinyl-3-nitro-5-acetylthiophene.

The results obtained are summarized in the following Table A, where the test substances according to the invention are given the same numbers as in the examples.

Table A test substance percentage of emerging healthy plants.

1 91 2 87 3 91 4 ’90 5 85 7 98 8 92 9 85 10 98 12 93 13 90 14 87 27 Mar: 96 (a) - known 68 (b) - known 75 (c) - known 74 untreated 67

Example 16

Seed Pickling Test for the Protection of Crop Plants against Phytopathogenic Pythium Fungi

CA 268823 B2

The test compounds are formulated into suitable formulations by pulverizing and then intimately mixed with kaolin at the desired concentration (see Table B). The beet seed is treated with these agents at a rate of 6 g of the composition per kilogram of seed and then sown in pans filled with soil heavily infested with Pythium spp. The sown dishes were kept in a greenhouse at 18-22 ° C and a relative humidity of 70-100% for 3 weeks. The results obtained are shown in Table 8 below. For comparative purposes, the test is also performed with the known 2-methylsulfinyl-4-methyl-5-nitrothiazole (a).

Table V test substance dose of active substance fall of seedlings in mg per kg of seeds in%

1 600 8 1 200 7 2 600 7 1 200 6 3 600 6 1 200 5 4 600 10 1 200 9 5 600 21 1 200 17 7 600 17 1 200 17 8 600 16 1 200 12 9 600 15 Dec 1 200 11 10 600 10 1 200 9 12 600. 0 1 200 0 13 600 3 1 200 1 14 600 23 1 200 20 May 27 Mar: 600 4 1 200 2 knows 600 57 1 200 45

untreated

CS 268823 82

Example 17

Toxicity to warm-blooded animals

It is determined lethal dose LD _5Q> and so that the test substance is orally administered to male mice and zjišiuje acute mortality. The following Table C shows the LD ₅₀ values found in mg / kg body weight.

The known compound (b) was also tested for comparative purposes (see Example 15).

Table C test substance

7 400 8 119 10 141 13 130 33 246 43 246

(b) - known

31.6

Example 18

Toxicity to warm-blooded animals

Using the so-called Ames test, mutagenic properties are detected. The Ames test is performed under normal standard conditions on Salmonella typhimurium TA 100 strain, both with metabolic activation (-S9) and without metabolic activation (+ S9). The results obtained are summarized in Table D below. For comparative purposes, the test is also performed with the known substance (c) (see Example 15).

Table D

Ames test test substance

- S9 + S9

5 7 8 9 10 12 13 23 33 40 44

(c) - known

CS 268823 82

Example 19

In vitro potency assay against Pyrenophora graminea

The test compound is added at a concentration of 3 and 10 ppm to a culture medium consisting of 1 X glucose, 0.2 X yeast extract (marmit), 0.5 X protein (peptone),

2.5 X agar-agar and 95.8 X water (all by weight) are placed in Petri dishes. Petri dishes are inoculated with the phytopathogenic fungus Pyrenophora graminea and stored at 20 ° C. After 48 hours, the inhibitory activity of the test compound on fungal growth was determined visually. The known compound (b) was also tested for comparative purposes (see Example 15). The results obtained are shown in Table E below.

Table E

test substance concentration in ppm inhibition of fungal growth in X 2 3 64 10 79 3 3 57 10 80 4 3 66 10 84 5 λ 54 10 89 6 3 54 10 77 7 3 59 10 83 8 3 49 10 72 31 10 77 33 10 83 35 10 76 39 10 81 43 10 72 47 10 74 51 10 71 52 10 71 53 10 83 66 10 84 72 10 70 78 10 86 79 10 80 82 10 80 85 10 73 86 10 76 94 10 70 (b) - known 3 0 10 37

control

Example 20

In an analogous manner to Example 19, the activity of the compounds of the invention against Fusarium culmorum was tested. The following compounds, when applied at 30 ppm, inhibit at least 75% fungal growth:

No. 2, 3, 5, , 7, n, 12, 13, 14, 19, 22, 23, 27, 29, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 4 ?, 43, <4, 45, 47, 51, 52, 53, 55, 57, 58, 61. 62, 64, 65, .67, 71, 72, 73, 74, 75, 7B, 79, 80, 81, 82, 85, 86, 87, 88, 89, 90, 91, 92 a 93,

Example 21

In the same manner as in the example, the activity of the compounds of the invention against Leptosphaeria nodorum is tested. The following compounds, when applied at 30 ppm, inhibit at least 85% of fungal growth:

No. 2, 3, 4, 5, 7, 9, 10, 12, 13, 14, 15, 17, 19, 20, 23, 27, 31, 32, 33, 34, 35, 36,

37, 40, 41, 42, 43, 44, 45, 47, 51, 53, 58, 63, 64, 65, 67, 71, 72, 73, 74, 75, 76, 85, 86, 87, 88, 89, 92 and 94.

Example 22

In the same manner as in Example 19, the activity of the compounds of the invention against Pythium splendens was tested. The following compounds, when applied at a concentration of 10 ppm, exhibit at least 95% inhibition of fungal growth:

No. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 39, 40, 41, 42, 43, 45, 46, 47, 48, 49, 50, 51, 52, 54, 56, 57, 58, 59, 60, 61, 66, 67, 68, 69, 70, 72, 74, 77, 78, 79, 80, 82, 83, 84, 85, 86, 89, 93, and 94.

Example 23

In the same manner as in Example 19, the activity of the compounds of the invention was tested against Rhizoctonia solani (Potato Root). The following compounds, when applied at 30 ppm, inhibit at least 75% fungal growth:

No. 2, 3, 4, 15, 19, 27, 33, 34, 36, 39, 42, 43, 52, 80, and 85.

Claims (8)

Fungicidal composition, characterized in that it contains, in addition to a liquid or solid carrier, a compound of the formula I (I) in which: R is C 1 -C 12 alkyl, C 2 -C 4 alkenyl or alkynyl, phenyl or benzyl; is cyano, formyl, C 2 -C 5 alkylcarbonyl or alkoxycarbonyl, optionally halogenated benzoyl or C 1 -C 4 alkylsulfonyl,. represents a hydrogen atom, a halogen atom, an amino group optionally substituted by one or two substituents selected from the group consisting of alkyl groups of 1 to 4 carbon atoms and alkylcarbonyl groups of 2 to 5 carbon atoms, triazolyl, imidazolyl, alkyl of 1 to 4 carbon atoms C 1 -C 4 alkoxy optionally substituted with C 2 -C 5 alkylcarbonyl, phenyl optionally substituted by halogen, phenoxy or phenylthio, or R 1 and R ₂ together with the vinylene group to which they are attached form a phenyl group optionally substituted with 1 to 2 halogens or nitro, X is cyano or formyl, n is 1 or 2, Y is C 1 -C 4 alkylthio; Z represents a hydrogen atom or a halogen atom, or Y and Z together constitute a sulfur atom, with the proviso that when Y and Z together do not represent a sulfur atom, and R ₂ forming together with the vinylene group to which they are attached, a phenyl group optionally substituted by one or two halogen atoms. 2. A composition according to claim 1, for treating soil or seed against phytopathogenic fungi, characterized in that, in addition to a liquid or solid carrier, it contains, as an active ingredient, a compound of the formula I as defined above. 1. Composition according to claim 1 or 2, characterized in that it contains, as active substance, a compound of the general formula II (II): R * represents an alkyl group having 1 to 4 carbon atoms, Y * is C 1 -C 4 alkylthio; R @ 1 represents a hydrogen atom or represents one or two halogen atoms. A composition according to claim 1 or 2, characterized in that it contains, as active ingredient, a compound of the general formula III (III): R, R 1, R 2, X and n are as defined in 1. 5. A composition according to claim 4, wherein the compound of formula (IV) is (IV) wherein: ^R l ' represents cyano, formyl, alkylcarbonyl, and the like C 2 to C 5 or benzoyl optionally substituted by halogen; n, R ₂ and R are as defined in point 1, or CS 268823 82 R 1 and R ₂ together with the vinylene group to which they are attached form a phenyl group optionally substituted by halogen or nitro. 6. A composition according to claim 5, characterized in that it contains as active ingredient a compound of the general formula V (V) in which: R 'is C 1 -C 4 alkyl, R 'represents cyano, formyl, acetyl, benzoyl or benzoyl substituted with one or two halogen atoms and R ₂ is hydrogen, halogen, alkyl or alkoxy radical containing 1 or 2 carbon atoms, _t, or amino optionally substituted with methyl. 7. A process according to claim 1, wherein the compound of formula (IX) is prepared R Z-C = C -C = C-Y (IX) in which ‘ R, R p, R ₂ , X, Y and Z are as in 1, reacted with an oxidizing agent. 8. The process of claim 7 wherein the oxidizing agent is hydrogen peroxide or a peroxycarboxylic acid.