Optically active derivatives of 2-imidazolin-5-ones, the way they are received, fungicidal composition, processing crops

 

(57) Abstract:

Optically active derivatives of 2-imidazolin-5-ones of General formula I, where W is an oxygen atom, M is an oxygen atom or sulfur; R1' and R2different and represent alkyl or phenyl radical, substituted by 1-3 groups selected from R6; R3- C1-2- alkyl, R4- H or phenyl, possibly substituted by 1-3 groups selected from R6; R5-N, except for the case when R4= H, or phenyl, possibly substituted by 1-3 groups selected from R6; R6- halogen or phenoxy, possibly substituted by a halogen atom, is produced by interaction of the compounds of formula II in which W is an oxygen atom, with a compound R3X, where X is a chlorine atom, bromine or iodine, or a sulfate group or alkylsulfonate or arylsulfonate. Compositions based on compounds of the formula I are used as antifungal drugs. 8 C. and 2 h.p. f-crystals, 11 PL.

The subject of the invention are optically active derivatives of 2-imidazolin-5-ones and 2-imidazolin-5-thiones with phytosanitary activity, the method of obtaining them, as well as new connections, if necessary, used as an intermediate in spasenija fungal diseases of crops through the use of these compounds.

Racemic derivatives of 2-imidazolin-5-ones and 2-imidazolin-5-thiones described in European patent applications 551048 and 599749 and in the international application to WIPO 94/01410.

Discovered that one of the optical isomers of these compounds have biological activity, which is much higher than the activity of another isomer and racemic mixtures.

The object of the invention therefore is to provide new compounds that are suitable to fight against fungal diseases of crops.

In particular, the object of the invention to provide new derivatives of 2-imidazolin-5-ones and 2-imidazolin-5-thiones, active in a reduced dose compared to the efficiency of racemic mixtures of derivatives.

According to the invention offers optically active derivatives of 2-imidazolin-5-ones and 2-imidazolin-5-thiones of General formula (I):

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in which

M denotes an oxygen atom or sulfur, or a radical, CH2if necessary, halogenated;

p denotes an integer of 0 or 1;

the sign * indicates that the carbon atom is asymmetric, the corresponding stereospecific configuration;

R1and R2are different and denote

alternalely, monoalkanolamines, alkanniny or alkynylaryl radical with 2 to 6 C-atoms, or

dialkylaminoalkyl or cycloalkenyl radical with 3 to 7 C-atoms, or

aryl radical including phenyl, naphthyl, thienyl, furyl, pyridyl, benzothiazyl, benzofuran, chinoline, ethenolysis or methylenedioxyphenyl, if necessary substituted by 1 to 3 groups selected from the group of values for R6; or

killkenny, aryloxyalkyl, arylthioureas or arylsulfonyl radical, and the terms "aryl" and "alkyl" have the above meanings; or

R1and R2together with the carbon to which they are bound, can form a loop, carbocycle or a heterocycle with 5 to 7 atoms, and these cycles can be combined with phenyl, where neobhodimosti substituted by 1 to 3 groups selected from the values for R6;

R3means:

hydrogen or C1-C2is an alkyl radical, if necessary halogenated, when p = 0 or (M)pdenotes the radical CH2;

C1-C2is an alkyl radical, if necessary halogenated, when (M)pdenotes an oxygen atom or sulfur;

R4does

a hydrogen atom; or

and the second, thiocyanation, alkenylphenol or alkenylphenol group with 2 to 6 C-atoms, or

dialkylaminoalkyl, alkoxycarbonyl or N-alkylcarboxylic group with 3 to 6 C-atoms, or N,N-dialkylanilines group with 4 to 8 C-atoms; or

aryl radical including phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, benzothiazyl, benzofuran, chinoline, ethenolysis, or methylenedioxyphenyl, if necessary substituted by 1 to 3 groups selected from the values for R6; or

killkenny, aryloxyalkyl, arylthioureas or arylsulfonyl radical, and the terms "aryl" and "alkyl" have the above meanings;

R5does

hydrogen except the case when R4= H, or

alkyl, allogeneically, alkylsulfonyl, halogenated.sulphonated radical with 1 to 6 C-atoms, or

alkoxyalkyl, alkylthiomethyl, acyl, alkanniny, alkynylaryl, halogenosilanes, alkoxycarbonyl, halogenocarboxylic, alkoxyalkanols, cyanoacetylene radical with 2 to 6 C-atoms, or

alkoxycarbonyl, alkyldiethanolamine, cyanoacetylene radika is, alkenylboronic, alkylcarboxylic radical with 3 to 6 C-atoms, or

cycloalkylcarbonyl radical with 4 to 8 C-atoms, or

phenyl radical; arylalkylamines radical, especially phenylacetylene and phenylpropionyl radical; arylcarboxylic radical, especially bentely radical, if necessary substituted by 1 to 3 groups selected from the values for R6; taylorsville radical; forelornly radical; pyridylcarbonyl radical; benzyloxycarbonyl radical; furfurylaminopurine radical; tetrahydrofurfurylamine radical; titillatingly radical; pyridinedicarboxylic radical; phenoxycarbonyl or phenylthiocarbamyl radical, and the phenyl, if necessary substituted by 1 to 3 groups selected among R6; alkyldiethanolamine radical; halogenlithiumcarbeniods radical; alkoxycarbonyl radical; sensitively radical; futuristically radical; tetrahydroprotoberberine radical; canimmediately radical; pyridylcarbonyl radical; or arylsulfonyl radical, or

carbamoyl radical, if necessary, mono - or Dieu or alkenylphenol group 3 - 6 C-atoms; or

alkoxyalkyl, allylthiourea or cyanoaniline group with 2 to 6 C-atoms, or

the phenyl, if necessary substituted by 1 to 3 groups of R6;

sulfamoyl group, if necessary, mono - or disubstituted by:

alkyl or halogenoalkanes group with 1 to 6 C-atoms, or

cycloalkyl, alkenylphenol or alkenylphenol group with 3 to 6 C-atoms, or

alkoxyalkyl, allylthiourea or cyanoaniline group with 2 to 6 C-atoms, or

the phenyl, if necessary substituted by 1 to 3 groups of R6;

alkyldiethanolamine group with 3 to 8 C-atoms or cycloalkylcarbonyl group with 3 to 7 C-atoms;

and R4and R5taken together, can also form with the nitrogen atom to which they relate, pyrrolidino-, piperidino, morpholino or piperazine derivatives group, if necessary substituted by alkyl with 1 to 3 C-atoms;

R6means:

halogen atom, or

alkyl, allogeneically, CNS, halogenosilanes, alkylthio, allogenicity or alkylsulfonyl radical with 1 to 6 C-atoms, or

cycloalkenyl, halogenically, alkenylacyl, alkyloxy, alkanity, alkylthio radical substituted alkyl or acyl radical with 1 to 6 C-atoms, or alkoxycarbonyl radical with 2 to 6 C-atoms;

- phenyl, phenoxy or pyridyloxy - radicals, and these radicals, if necessary substituted by 1 to 3 identical or different groups chosen among R7;

R7means:

is a halogen atom selected from fluorine, chlorine, bromine, iodine, or

is an alkyl radical, linear or branched, containing 1 to 6 carbon atoms, or

- alkoxy - or alkylthio radical, linear or branched, containing 1 to 6 carbon atoms, or

- halogenoalkane or allogeneically radical, linear or branched, containing 1 to 6 carbon atoms, or

- nitrile group, or

- the nitro-group.

The invention also relates to acceptable in agriculture salt forms of the above compounds.

According to a preferred variant of the invention, the optically active compounds according to the invention correspond to the formula (II):

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in which the substituents have the above for formula (I) values.

In particular, preferred compounds according to the invention of the formula (II) in which W represents an oxygen atom.

The method of obtaining compounds of formula (I) described below according to the same values as above, unless they are listed with other definitions.

Option a:

First stage:

In the first stage of this option describes the preparation of optical isomers of formula (I) of optically pure or highly enriched in one enantiomer of the amino acids. Under optically active compound realize highly enriched in a specific enantiomer of the compound containing at least 80%, preferably 95% of this enantiomer.

The optical isomers of formula (I) are obtained according to the three kinds of methods, depending on the values of the group (M)p-R3.

1) Obtaining the compounds of formula (I) in which p = 1 and M = S and W = O.

The compounds of formula (I) in which p = 1 and M = S and W = O, is produced by the interaction of the compounds of formula (III):

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in which W represents an oxygen atom, with a compound of formula R3X, where X denotes a chlorine atom, bromine or iodine, or a sulfate group or alkylsulfonate or arylsulfonate, and "alkyl" and "aryl" shall have the meanings indicated above for R1and R2. The reaction is carried out in a solvent and in the presence of a base. As a basis you can use the alcoholate, tert.-butyl potassium; alkali hydroxide is but to use ethers, cyclic ethers, complex alkalemia ethers, acetonitrile, alcohols with 1 to 3 C-atoms; aromatic solvents; for example, tetrahydrofuran, at a temperature of from -5oC to +80oC.

One variant of the method described above is a one-step method, as described in European patent application 551048. This method consists in using directly isothiocyanate formula (IV), which is treated with a compound of the formula (V) in a solvent and in the presence of a base, as described above. The intermediate compound of formula (IIIa) in salt form are not allocated, and the right is treated with a compound of the formula R3X, in which X has the above value:

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The compound of formula (III) in which W represents an oxygen atom, can be obtained by the reaction of cyclization between isothiocyanato formula (IV):

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in which R represents a C1-C4- alkyl,

and the compound of the formula (V):

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The cyclization reaction can be realized in two ways:

- heat: in this case, the mixture of reactants is heated at a temperature of 110 - 180oC in aromatic solvent such as toluene, xylene, chlorobenzene;

- the primary environment: the cyclization reaction is carried out in prisutstyovie Amin. Under these conditions, the cyclization is carried out at a temperature of from -10oC to +80oC. the solvent can be used especially ethers, cyclic ethers, alcohols, esters, DMF, DMSO.

Isothiocyanates of the formula (IV) can be obtained according to one of the methods cited in Sulfur Reports, volume 8(5), S. 327 - 375 - amino acid of formula (VI) through a complex aminoether formula (X):

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well-known to the specialist.

Complex amino esters of structure (X) can be obtained in itself known:

by diastereoselective amination prehiring connection with the subsequent removal of the protection of chiral ligament (la copule), as described by R. S. Atkinson and al., Tetrahedron 1992, 48, C. 7713 - 30;

by separation of the corresponding racemate with a chiral compounds, as described in Y. SUGI and S. Mutsui, Bull, Chem. Soc. Japan, 1969, 42, S. 2984 - 89.

- by esterification to a complex ester of chiral acids, as described by D. J. CRAM and researcher. J. Am.Chem.Soc. 1961, 83, C. 2183-89.

(+)-Methyl-(2S)-2-amino-2-phenyl-propionate is obtained by processing videolooking of the hydrochloride with I equivalent of sodium bicarbonate, then extraction with dichloromethane. It is a slightly viscous b is the moat of the formula (I), in which p = 1 and M = O and W = O.

The compounds of formula (I), in the second p = 1 b M = O and W = O, is obtained by introducing into the interaction of the corresponding compounds of formula (I) in which p = 1 and M = S, according to the method described in European patent application 599749, with an alcohol of formula R3OH, in a solvent, in the presence of a strong base, and the temperature is 50 - 80oC. as a strong base, you can use the alcoholate of an alkali metal, R3O-Met.+where Met.+denotes an alkali or alkaline earth metal, a hydroxide of an alkali metal or strong organic base. The reaction is carried out, preferably using as a solvent an alcohol R3OH and using the corresponding sodium alcoholate R3O-Na+as the base.

3). Preparation of optical isomers of formula (I) in which p=0

The compounds of formula (I) in which p=0 and R3denotes a hydrogen atom, is obtained from the compounds of formula (VII):

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by introducing its interaction with dimethylformamide-dimethylacetal (DMFDMA). The reaction is carried out at a temperature of 10-100oC, in excess DMFDMA.

The compound of formula (VII) are obtained from the compounds of formula (VIII)0oC in a solvent, representing a simple cyclic or acyclic ether, if necessary in the presence of a base. The basis is chosen among the nitrogen-containing organic bases such as triethylamine or pyridine.

The compounds of formula (VIII) can be obtained from amino acids of formula (VI), whereas the method described S. Levine in J. Am. Chem. Soc. 1953, T. 76, S. 1392.

Optically active compounds of formula (I) in which R3represents C1-C2is an alkyl radical, if necessary halogenated, and in which p = 0 or p and M = CH2receive from the compounds of formula (IX):

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in which R3represents C1-C3is an alkyl radical, by reacting it with a compound of formula (V) under the conditions specified by analogy with the method presented in the article by J. P. Branquet and others in Bull. Soc. Chem. de France, S. 2942-2954.

In the same article the way to work, according to which the compound of formula (IX) can be obtained from amino acids of formula (VI).

The second phase.

For this second stage describes a method of obtaining optically pure or highly enriched - amino acids of formula (VI) used in the previous stage. Prov.diastereoselective synthesis, then remove the chiral bridge, as described M. Chaari, A. Jenni, J. P. Laverque and P. Viallefont in Tetrahedron, 1991, T. 4, S. 4619-4630;

- either by enzymatic decomposition of racemic amide by the method described in the following references: R. M. Kellog, E. M. Meijer and researcher. J. Org. Chem. 1988, 53 so, 1826-1828; D. Rossi and A. Calcagni, Experimentia, 1985, T. 41, S. 35-37.

either by hydrolysis of the chiral precursor amino acids, for example:

- formelementname structure (XI), such as described Mac. KEWZIE and CLOUGH, J. Chem. Soc. 1912, C. 390-397 or DJCRAM al. J. Am. Chem. Soc. 1961, 83, C. 2183-2189;

- as structure (XII), such as described in published patent application UK N 1201169:

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Compounds of formula (XI) or (XII) can be obtained by separation of the corresponding racemic mixture with a chiral compounds, as described Mac. KENZIE and GLOUGH, J. Chem. Soc. 1912, C. 2183-2189, for compound (XI) or as described in published international patent application N 9208702, for compound (XII).

Option B.

According to the second variant of the method of obtaining the optical isomers of formula (I), is obtained from the corresponding racemic compounds by high-performance liquid chromatography on a chiral stationary phase. Preferred chiral stationary FA is but the means, described in three patent applications, cited above, at page 1 of this specification.

The object of the invention are also novel optically active compounds, especially suitable as an intermediate in the formation of compounds of formula (I). These intermediate compounds correspond to formula (III), (IV); (VI) (VII) (VIII); (X).

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in which R1- R5have the same values as specified in the General formula (I) of the invention:

and the formula (IX):

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in which R1and R2have the above meaning; and R3represents C1-C3is an alkyl radical, if necessary halogenated;

and the formula (HB):

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in which R1has the above meaning, R6denotes phenyl, phenoxy or pyridyloxy-radicals, and these radicals, if necessary substituted by 1-3 identical or different groups chosen among R7such as defined above.

The invention also relates to compositions for protecting plants from fungal diseases, containing, along with one or more solid or liquid carriers, which is acceptable in agriculture, and/or surface-active agents, also praml is rmula (I).

In fact for practical use of the compounds according to the invention are rarely used by themselves. Often these connections form part of the compositions. These compositions are used as antifungal preparations that contain the active beginning of the connection according to the invention, such as described above, in a mixture with a solid or liquid media, which is acceptable in agriculture, and surface-active agents, also acceptable in agriculture. In particular, use the usual imported inert carriers and conventional surface-active agents. These compositions are also part of the invention.

These compositions can also contain any kind of other ingredients, such as, for example, protective colloids, adhesives, thickeners, thixotropic agents, penetration agents, stabilizers, complexing agents, etc., Generally used in the invention compounds may be combined with any solid or liquid additives corresponding to the usual ways of making the formulation.

Usually the compounds according to the invention contain about 0.05-95% (weight) of the compounds according to the invention (called later "the acting is OSTO-active agents.

The term "media" in this presentation represent organic or inorganic, natural or synthetic material with which the compound is combined to facilitate its application to the plant seeds or to the soil. This carrier is therefore generally inert and should be acceptable in agriculture, especially for the processing plants. The carrier can be solid (clays, natural or synthetic silicates, silica, resins, waxes, solid fertilizers, and so on) or liquid (water, alcohols, especially butanol, and so on).

Surface-active agent can be an emulsifier, dispersant or wetting agent of ionic or non-ionic type or a mixture of such surface-active agents. Can be called, for example, salts of polyacrylic acids, salts of lignosulfonic, salt phenolsulfonic or naphthalenesulfonic, polycondensate of ethylene oxide with fatty alcohols or with fatty acids or fatty amines: substituted phenols (especially ALKYLPHENOLS or kilfenora), salts of esters sulfonating acids, derivatives of taurine (especially alkylarene), complex phosphate esters polyoxyethylene alcohols or phenols, esters of fatty acids and polyhydric alcohols, the production of one surface-active agent is usually necessary, when the connection and/or the inert carrier is insoluble in water and vector agent application is water.

So, therefore, the compositions for agricultural use according to the invention can contain start acting according to the invention in a very wide range, up to 0.05 to 95 wt.%. The content of surface-active agent is preferably 5-40 wt.%.

These compositions according to the invention are in different forms: solid or liquid.

As solid forms of compositions may be called powders for dusting (containing compounds, which can reach up to 100%) and granules, especially those obtained by extrusion, compacting, application of granular media, granulation from a powder, the content of compounds in these granules can be 0.5-80% in these latter cases, tablet or foaming tablets.

The compounds of formula (I) can still be used in the form of powders for dusting; you can also use a composition comprising 50 g of active start and 950 g of talc; you can also use a composition comprising 20 g of active start, 10 g of finely ground dioxide BAP is este form of liquid compositions or intended to constitute liquid compositions during application can be called solutions in particular water-soluble concentrates, emulsifiable concentrates, emulsions, concentrated suspensions, aerosols, wetting powders (or powders for comminution), pastes, gels.

Emulsifiable or soluble concentrates most often contain 10-80% of the current beginning; and ready-to-use emulsions or solutions contain, as for them, of 0.001-20% of applicable beginning.

Most often, the emulsifiable concentrates can contain, when necessary, 2-20% of appropriate additives, as the above-mentioned stabilizers, surface-active agents, penetration agents, corrosion inhibitors, dyes or adhesives.

From these concentrates by dilution with water it is possible to prepare emulsions of any desired concentration, which are particularly suitable for application to crops.

As the example below shows the composition of several emulsifiable concentrates:

Example EC 1:

active principle of 400 g/l

dodecylbenzensulfonate alkali metal - 24 g/l

Nonylphenol, ethoxylated with 10 molecules of ethylene oxide - 16 g/l

cyclohexanone - 200 g/l

aromatic solvent to a total volume of 1 liter

According to another f the new vegetable oil - 25 g

a mixture of alkylarylsulfonate and simple polyglycolide ester with fatty alcohols - 100 g

the formamide - 50 g

xylene - 575 g

Concentrated suspensions also apply for comminution, is prepared so as to obtain a liquid stable, non-degradable product, and they usually contain 10-75% of the applicable early, 0.5 to 15% of surface-active agent, 0.1 to 10% of thixotropic agents, 0-10% of appropriate additives, as antispyware, corrosion inhibitors, stabilizers, penetration agents and adhesives, and as carrier, water or an organic liquid in which the active principle is little soluble or not soluble: some solid or organic substances or inorganic salts can be dissolved in the carrier, to prevent sedimentation, or as anthela water.

As an example, shows the composition of the concentrated suspension:

Example KS 1:

current start - 500g

polyethoxysiloxane muistiinpanoista - 50 g

polyethoxysiloxane alkyl phenol - 50 g

polycarboxylic sodium - 20 g

the ethylene glycol - 50 g

organopolysiloxane oil (non) - 1 g

polysaccharide - 1.5 grams

water began acting, and they usually contain, in addition to solid carrier, from 0 to 30% of wetting agent, 3-20% dispersant, and, when necessary, 0.1 to 10% of one or more stabilizers and/or other additives, as penetration agents, adhesives, or prevent clumping agents, dyes, etc.

To obtain powders for comminution or wettable powders thoroughly mixed with the existing start, in appropriate mixers, with the additives and crushed using mills or other suitable grinders. Thus obtained powders for comminution, wettability and suspenderbelt are preferred; they can be suspended in water to any desired concentration and these suspensions are preferably used in particular for application to the leaves.

Instead of wettable powders can be implemented pasta. Conditions and methods of implementation and use of these pastes are similar to those for wettable powders or powders for comminution.

As examples of the various formulations of wettable powders (or powders for comminution) (SP).

Example SP 1:

current start - 50%

ethoxylated fatty alcohol/lubricant/ - 2,5%

etok the respective start - 10%

synthetic oxo-alcohol branched type, C13, ethoxylated with 8-10 units of ethylene oxide (wetting agent) - 0,75%

neutral calcium lignosulfonate (dispersant) - 12%

calcium carbonate (inert filler) to - 100%

Example SP 3:

This wettable powder contains the same ingredients as in example SP 2, in the following amounts:

active principle - 75%

the wetting of 1.50%

dispersant - 8%

calcium carbonate (inert filler) to - 100%

Example JV 4:

active principle - 90%

ethoxylated fatty alcohol (wetting agent) - 4%

the ethoxylated phenylethanol (dispersant) - 6%

Example JV 5:

current start - 50%

the mixture of surface-active anionic and non-ionic substances (wetting agent) - 2,5%

sodium lignosulphonate (dispersant) - 5%

cholinseterase clay (inert carrier) - 42,5%

Aqueous dispersions and emulsions, for example compositions obtained by diluting with water wettable powder or an emulsifiable concentrate according to the invention, included in the scope of the present invention. Emulsions can be of the type water-in-oil or oil-in-water and may have a thick consistency, to ergonamic in the water of the granules, also included in the scope of the invention.

These dispersible granules with an apparent density is typically about 0.3 to 0.6 have a particle size of usually about 150-2000 and preferably 300-1500 mm.

The content of active beginning in these granules is usually about 1-90%, and preferably 25-90%.

The rest of the granulate formed essentially of a solid filler and, if necessary, surface-active additives, which give the granulate properties of the dispersive ability of the pigment in water. These granules can be essentially of two different types, depending on whether soluble or not in the water holding the filler. When the filler is water-soluble, then it may be inorganic or preferably organic. Excellent results are obtained with urea. In the case of insoluble filler, it is preferably inorganic, such as kaolin or bentonite. Then he preferably accompanied by surface-active agents (2-20 wt.% the pellet), more than half of which, for example, formed by at least one dispersant, mainly anionic, such as polynaphthalene alkali or alkaline earth metal lignosulfonate saloon alkylnaphthalenes alkali or alkaline earth metal.

In addition, although it is not mandatory, you can add other additives, such as anti-foam agents.

The granulate according to the invention can be obtained by mixing the necessary ingredients, then by granulation according to (drazhirovanie, pseudovariety layer, the atomizer, extrusion and so on). Usually finish by crushing followed by screening to a particle size selected in the above range. You can still use the granules obtained as above, then soaked containing the active principle of composition.

Preferably, the granulate is produced by extrusion, working as described in the examples below.

Example GD 1: Dispersible granules.

In mixer blend of 90 wt.% the current start and 10% urea in the form of beads. The mixture was then crushed in a rod mill. Get the powder, which is moistened with about 8 wt.% water. Wet powder ekstragiruyut in the perforated drum extruder. Get a granulate which is dried, then crushed and sieved to leave only the granules of 150-2000 mm.

Example 2 DG: Dispersible granules

In the mixer mixing the) - 2%

dispersant (polynaphthalene sodium) - 8%

inert, water-insoluble filler (kaolin) - 15%

This mixture granularit in the fluidized bed in the presence of water, then dried, crushed and sieved to obtain granules with a size of 0.15-0,80 mm

These boundaries can be used individually, in the form of a solution or dispersion in water to obtain the desired dose. They can also be used for making associations with other active principles, especially fungicides, and these latter are in the form of wettable powders or granules, or aqueous suspensions.

In regard to compositions adapted for storage and transportation, they preferably contain from 0.5 to 95% (by weight) of the active substance.

The subject invention also is a method of cultivation of crops affected or can be affected by fungal diseases, characterized in that, for the prevention or treatment applied an effective amount of the optically active compounds of formula (I).

The compound of formula (I) preferably is applied at doses of 0.005 to 5 kg/ha, most preferably from 0.01 to 1 kg/ha

The following examples illustrirovannyj derivatives characterized by using at least one of the following spectral methods:

1H-NMR spectrometry; 13C-NMR spectrometry; IR spectrometry and massspectrometry, as well as the usual methods of measuring rotational abilities. The excess of enantiomers determined either by using high-performance liquid chromatography or NMR.

In table.1-6 phenyl, methyl and ethyl radicals denote, respectively, Ph, Me, Et.

Example 1: (+)-(4S)-4-Methyl-2-methylthio-4-phenyl-1-phenylamino-2 - imidazolin-5-Oh (compound No. 1).

In a reactor with a capacity of 20 l, through which is passed a current of argon, is injected 682 g (is 3.08 mol) (+) methyl-[2S]-2-phenyl-2-isothiocyanatobenzene dissolved in 4 l of anhydrous tetrahydrofuran. Cooled to 15oC. for 30 min, keeping the temperature 15-18oC, poured a solution of 343 g (is 3.08 mol) of phenylhydrazine in 2 l of tetrahydrofuran. The environment is maintained with stirring for 40 min, then cooled to 0oC. for 1 h, all the while maintaining the temperature at 0oC, poured a solution of 346 g (is 3.08 mol) of tert.-of potassium butyl 4 l of tetrahydrofuran. Stirring of the reaction medium continued for 2 h at 0oC and observe the formation of sludge light pink color. Within 15 min, keeping the temperature at 0 to 3oC, tide is within 2 hours The reaction mixture is poured into 5 l of water. After decanting, the aqueous phase is extracted 3 times with 3 l of ethyl acetate. The combined organic phases are washed with 5 l of water, dried over magnesium sulfate, and then concentrated under reduced pressure. Receive a 1099 solid brown color. It is recrystallized from 2 l of toluene. After drying receive 555 g (+) (4S)-4-methyl-2-methylthio-4-phenyl-1-phenylamino-2 - imidazolin-5-it is in the form of friable solids white, melting at 138oC. Yield = 58%; +61,1o[ 2,9o] {C = 0,86, ethanol}; the content of enantiomer excess (E. E.) > 98%.

Similarly receive the following similar to the compounds of formula IIA (see tab. 1).

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Example 2: (+) (4. S)-4-Methyl-4-phenyl-1-phenylamino-2-thiohydantoin (compound # 7)

In a three-neck flask with a capacity of 100 ml with an atmosphere of dry nitrogen injected 0.7 g (0,00316 mol) (+) (2S)-methyl-2-isothiocyanato-2-phenyl - propionate, diluted with 15 ml of anhydrous tetrahydrofuran. At 20oC at one time poured of 0.32 ml (0,00316 mol) of phenylhydrazine, diluted with 5 ml of tetrahydrofuran. The temperature is increased to 2oC. the Medium was incubated for 30 min under stirring with a magnetic stirrer. Appears ocaml water. After decanting, the organic phase is extracted 3 times with 20 ml diethyl ether. The combined organic phases are washed 2 times with 30 ml water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained solid residue chromatographic on a column of silica gel using an eluting the mixture of heptane and ethyl acetate in a ratio of 50/50.

Obtain 0.55 g (+) (4S)-methyl-4-phenyl-1-phenylamino-2 - thiohydantoin in a solid beige color, melting at 167oC. Yield = 58%; +86o[ 3,2o] [C = 0.8, methanol].

Example 3: (+)-Methyl-(2S)-2-isothiocyanato-2-phenyl-propionate (compound No. 8)

In a reactor with a capacity of 20 l enter 780 g (3.61 mol) of (+) of the hydrochloride of methyl-(2S)-2-amino-2-phenyl-propionate, then 3.4 l of water. The temperature is brought to 20oC. Add 3.4 liters of toluene, and then for 1 h add portions 911 g (10,8 mol) of sodium bicarbonate. The temperature is reduced to 8-9oC. is Poured within 2 h 276 ml (3,6 1 mol) of thiophosgene. The reaction is accompanied by the release of gases and temperature rise, which reaches 24oC at the end of prilipanie. Wednesday was incubated for 2 h with stirring. After decanting, the aqueous phase is extracted with 2 l of toluene. Objresult under reduced pressure. Receive 682 g of (+)-methyl-(2S)-2-isothiocyanato-2 - phenyl-propionate in the form of a slightly colored oil. Yield = 85%; +16o[ 6,4o] [C = 0,78, chloroform].

Similarly receive the following similar to the compounds of formula IVa (see tab.2).

< / BR>
Example 4: (+) of the Hydrochloride of methyl-(2S)-2-amino-2-phenyl-propionate (compound No. 9).

In a reactor with a capacity of 10 l load 611 g (3.7 mol) of (+)-2-amino - 2-phenyl-propionic acid, which is added to 5 l of methanol. The resulting white suspension for 2 h, poured 819 ml (11,22 mol) of thionyl chloride. At the end of prilipanie temperature reaches 58oC. See significant outgassing, and gases trap with dilute sodium hydroxide solution. Wednesday heated at 65oC for 14 hours, the Solution is then concentrated under reduced pressure. The obtained solid residue is treated with 1 l of toluene, filtered, then dried under vacuum. Get 762 g of (+)-chloro-hydrate methyl-(2S)-2-amino-2-phenyl - propionate in the form of Porsche white, melting at 162oC. Yield = 62%; +53,3o[3,3] [C=0,75, water].

Similarly receive the following similar to the compounds of formula Xa (see tab. 3).

< / BR>
Example 5: (+) (4,S)-4-Me, in an atmosphere of dry nitrogen injected 80 ml of methanol, then 0.74 g (to 0.032 mol) cut small pieces of sodium. Then add 5 g (0,016 mol) (+) (4S)-4-Methyl-2-methylthio-4-phenyl-1-phenylamino-2-imidazolin-5-it. Refluxed for 20 hours. Cooled to room temperature, then acidified with 0.5 ml of acetic acid. The methanol is removed by distillation under reduced pressure, then the residue is treated with 50 ml of diethyl ether, washed 3 times with 40 ml water, dried over magnesium sulfate, and the solution was concentrated under reduced pressure. Get reddish honey, which is purified by chromatography on a column of silica, elwira using a mixture of heptane to ethyl acetate in the ratio of 70:30.

Get 2 g (+) (4S)-4-methyl-2-methoxy-4-phenyl-1-phenyl-amino-2 - imidazolin-5-it is in the form of a light pink powder, melting at 132oC. Yield = 42%; +53,1o( 2,4o) (C = 1 in methanol) E. E. > 98%.

Similarly receive the following similar to the compounds of formula Ib: (see tab.4). ).

< / BR>
Example 6: (+) (2S)-2-Amino-2-phenyl-propionic acid (compound No. 10)

In the autoclave of 1 liter consistently give 22 g (0,115 mol) (+) (5S) -5-methyl-5-s to room temperature the solution is concentrated under reduced pressure. The obtained solid white is treated with 100 ml of ethyl acetate for 2 h, then filtered and dried in vacuum at 80oC. Receive a 10.5 g (+) (2S)-2-amino-2-phenyl-propionic acid as a white powder, which has a decomposition temperature 266oC. Yield = 55%; +71,9oC (3,1o) (C=0.8 in 1H. hydrochloric acid).

In the same way get the following analogous compounds of formula VIa (see tab.5).

< / BR>
Example 9 illustrates the formation of compounds of formula (XII).

Example 9: 5-S(+)-5-Methyl-5-phenyl-hydantoin (compound No. 35)

To a stirred suspension 70,0 (0,368 mol) of (5R, S)-5-methyl-5-phenyl-as in 2000 ml of water is added 5.6 g (0,139 mol) of sodium hydroxide. The resulting solution is brought to a temperature 40oC, then add to 44.6 g (0,368 mol) of R-(+)-S-methylbenzylamine. The resulting solution was incubated at 50oC for 0.75 h, and after 3 min, the precipitate appears white. After heating the reaction mixture is left to crystallize for 24 h, and then the crystals are filtered, washed with water in an amount of 70 ml, suck in air for 2 h, obtaining 45 g of solid white, which added to 220 ml of 1 N. hydrochloric kyaut with 100 ml of water, sucked off, and then dried under reduced pressure at 50oC for 15 h Thus obtained 23 g (0,121 mol) 5-S(+)-5-methyl-5-phenyl-hydantoin in the form of friable solids white, melting at 242oC. Yield = 66%; +113o(C=1.0 in ethanol).

In the same way, but using S - ( -) - methylbenzylamine get a 5-R(-)-5-methyl-5-phenyl-as in the form of friable solids white, melting at 248oC. Yield = 54%; +120o(C=1.0 in ethanol).

Similarly receive the following similar to the compounds of formula XIIa (see tab.6).

< / BR>
The examples below illustrate the optically active derivatives of the formula (I) obtained according to variant B of the method of obtaining.

Example 7: the Separation of (+)- and (-)-enantiomers of the compounds of the following formula (compound No. 1 and 2):

< / BR>
The corresponding racemic compound receive according to the method similar to that described in example 1 of European patent application 551048, already cited. This racemic compound dissolved in a mixture for elution consisting of n-heptane, isopropanol and dichloromethane, in the respective weight ratio of 93.5% and 2%.

2,3 ml of the thus obtained mixture Ikami:

- column type PIRKLE, with a diameter of 10 mm and a length of 250 mm;

- filler: silica gel, 5 μm, 100 angstroms, containing ion in the n-phenylglycine.

The feed rate of 10 ml/min and used detector is a UV detector at 250 nm. Enantiomerically pure compounds extracted by fractionation and concentration of the pure fractions.

In table.7 presents the physical characteristics of the resulting enantiomers, namely the melting temperature (i.e. square), rotational capacity measured in degrees for compounds dissolved in ethanol, at a concentration of 0.5 g per 100 ml; and the retention time of tR.

Example 8: Separation of (+)- and (-)-enantiomers of the compounds of the following formula (compound No. 3 and 4)

< / BR>
The corresponding racemic compound receive according to the method similar to that described in example 1, already cited European patent application 599749. The corresponding (+) - and (-)-enantiomers (respectively connect N 3 and 4) are obtained as described above. Injected in chiral column volume is 1.5 ml Rotational ability was measured after dissolving the compounds in methanol and this value is presented along with other physical features, the Oia following formula (compound No. 5 and 6)

< / BR>
The corresponding racemic compound receive according to the method similar to that described in example 1, already cited in the above example, European patent application 599749. The corresponding (+)- and (-)-enantiomers (respectively, compounds No. 5 and 6) receive, acting in the same manner as described above. The results obtained are presented in table.9.

The absolute configuration of compounds No. 1 to 4 is determined by chemical correlation with the absolute configuration of the corresponding - amino acids described in the literature. The absolute configuration of N compounds 5 and 6 was determined by x-rays.

The following examples illustrate the fungicidal properties of the compounds of formula (I) according to the invention N 1 - 6: 11 - 14, 25 - 28. In these examples, the corresponding racemic mixture enantiomeric compounds 1 and 2 denote as (1+2). Similarly, the corresponding racemic mixture of compounds 3 and 4 indicate (3+4). In General, the corresponding racemic mixture enantiomeric compounds "n" and "n+1" is designated as n + (n+1).

Example B 1: Test in vivo on Puccinia recondita smut on wheat).

Produced by intensive dispersion aqueous suspension of the test action is N. 80 (oleate polyoxyethyleneglycol derived sorbitan) when diluted with water to 10%:

- add 60 ml of water, 0.3 ml

Tested active principle is either one of the two enantiomers according to the invention or the corresponding racemic mixture.

This aqueous suspension is then diluted with water to obtain the desired concentration of the active beginning.

Wheat varieties Tabent, cups, sown on a substrate of peat with pozzolan 50/50 handle at the stage height of 10 cm by spraying the above aqueous suspension.

After 24 h of wheat put the water spraying the spore suspension (100 000 spores/cm3); this suspension obtained from infected plants. Then the wheat is placed for 24 h in an incubation chamber with a temperature of about 20oC and the relative humidity is 100%, then within 7-14 days is maintained at a relative humidity of 60%.

Monitoring the status of the plant carried out between the 8th and 15th day after infection, by comparison with the untreated control sample. Then determine the concentration of the test current started, CI75(expressed in M. D. ), in which the observed inhibition of 75% of the disease. The results are presented in table. 10.

Example B 2: Test in vivo on Ph the beginning of the current, having the following composition:

the active principle is 60 mg

surface-active agent tween 80 (oleate polyoxyethyleneglycol derived sorbitan) when diluted with water to 10% - 0.3 ml

add water to 60 ml

Tested active principle are among the same compounds as in the previous example.

This aqueous suspension is then diluted with water to obtain the desired concentration of the active beginning.

Tomato plants (variety Marmande) cultivated in pots. When these plants reach the age of 1 month (stage 5-6 leaves, the height of 12-15 cm), they are treated by spraying viseporodicnog water suspension with different concentrations of the test compounds.

After 24 h each plant infected by spraying a water suspension of spores (30 000 spores/cm3) Phytophthora infestans.

After that infect tomato plants are incubated for 7 days at a temperature of about 20oC in a saturated humidity atmosphere.

After 7 days after infection, and compare the results obtained in the case of treated subjects active principle of the plant, obtained in the case used as control plants. Then determine the 75% of the disease. The results are presented in table. 11.

1. Optically active derivatives of 2-imidazolin-5-ones of General formula I

< / BR>
where W represents an oxygen atom;

M denotes an oxygen atom or sulfur;

R1and R2are different and represent alkyl or phenyl radical, if appropriate, substituted by 1 to 3 groups selected among R6;

R3represents C1- C2is an alkyl radical;

R4denotes a hydrogen atom or a phenyl radical, if necessary, substituted 1-3 two groups selected among R6;

R5denotes hydrogen, except when R4= H, or a phenyl radical, if appropriate, substituted by 1 to 3 groups selected among R6;

R6denotes a halogen atom or phenoxy radical substituted by a halogen atom selected from among fluorine, chlorine, bromine or iodine.

2. Optically active compounds on p. 1, formula II

< / BR>
where R2- R6have the values listed in paragraph 1.

3. Optically active compounds of formula II under item 2, in which W represents oxygen.

4. Connection on p. 3, characterized in that it is a (+) - S - enantio4is phenyl; R5and R6- the hydrogen atom.

5. Method of producing compounds of the formula I, in which M = S and W = 0, according to any one of paragraphs.1-4, characterized in that interact the compounds of formula III

< / BR>
in which W represents an oxygen atom,

with the compound of the formula R3X, in which X denotes a chlorine atom, bromine or iodine, or a sulfate group, or alkyl of sulfonyloxy or arylsulfonyl-oxygraph, in a solvent and in the presence of a base at a temperature from -5 to +80oC.

6. Optically active compounds of General formula

< / BR>
in which R1- R5have the meanings mentioned for the General formula I on p. 1,

as intermediates in obtaining the compounds of formula I.

7. Connection on p. 6, characterized in that in formula III, R1denotes phenyl and R2is methyl.

8. Fungicidal composition comprising, together with one or more solid or liquid, which is acceptable in agriculture, carriers and/or surface-active agents, also acceptable in agriculture, the active principle is derived imidazolin-5-she, characterized in that the active agent contains a compound of the formula shall be affected by fungal diseases, by applying active compound - derived imidazolin-5-she, characterized in that the active compounds are used optically active compound of the formula I according to any one of paragraphs.1 to 4 in an effective amount.

10 Method of cultivation of crops under item 9, characterized in that compounds of the formula I is applied at doses of 0.005 to 5 kg/ha, preferably 0.01 to 1 kg/ha

 

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The invention relates to certain new compositions and methods of using the known soil fungicide and plant growth regulator, 3-hydroxy-5-methylisoxazole, including, in addition, specific hydrate calcium salts of this compound

The invention relates to 1-alkyl, 1-alkenyl, and 1-alkynylaryl-2-amino-1,3-propandiol formula 1:

< / BR>
where R is

< / BR>
< / BR>
R5represents a group of the formula:

CH3(CH2)mCC-, CH3(CH2)mCH CH-,

CH3(CH2)mCH2-CH2-,< / BR>
,< / BR>
m is from 3 to 15 and n is from 0 to 12

The invention relates to 1-alkyl, 1-alkenyl or 1-alkynylaryl-2-amino-1,3-propandiol formula I

RCH (OR1)CHN(R2R3)P4whereOSO

R5-CH3(CH2)mCC,

CH3(CH2)mCH=CH-, CH3(CH2)mCH2-CH2-,-CH2(CH2)nCC-,

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R1is hydrogen orR6where R6is hydrogen, alkyl, alkoxy, or OCH2-;

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where R9and R10independently are hydrogen or alkyl

The invention relates to methods for isoxazolone derivatives of General formula I

where R1is a hydrogen atom, a halogen atom or an alkyl group containing 1-6 carbon atoms;

R2is a hydrogen atom; an alkyl group containing 1-4 carbon atoms; phenyl group which is unsubstituted or which is substituted by at least one of substituents (a), defined below; or a heterocyclic group, which contains 5 or 6 ring atoms, of which 1 is a nitrogen atom or sulfur heteroatom;

R1and R2together form a group of the formula

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< / BR>
in which W is sulfur atom or oxygen or the group S = O;

A is O or S;

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where R1,2=C2H5; R3=C_< / BR>
R1,2=CH3; R3=C_< / BR>
R1,3=C2H5; R2=C_< / BR>
R1,3=CH3; R2=C_

The invention relates to derivatives of 2-imidazolin-5-ones or 2-imidazolin-5-thiones General formula

< / BR>
in which W is sulfur atom or oxygen or the group S = O;

A is O or S;

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