Stereo isomers of n-(r)-1-aryl-ethyl)-1-alkyl-2,2-dichlorocyclopropane carboxamide

0001The present invention relates to new stereoisomers of N- (R) - (1-aryl-ethyl) -1-alkyl-2,2-dichloro-cyclopropanecarboxamides, a process for their preparation and their use for combating fungi.

0002It is already known that mixtures of isomers of certain cyclopropanecarboxamides, such as. B. of N- (1- (4-chlorophenyl) ethyl) -2,2-dichloro-1-ethyl-3-methylcyclopropanecarboxamide have fungicidal properties (cf. EP-A 170 842 / US Pat. No. 4,710,518 ). However, the action of the known compounds is not satisfactory in all respects.

0003Certain optically active forms of substituted cyclopropanecarboxamides have also become known (cf. EP-A 257 448).

0004New stereoisomers of N- (R) - (1-arylethyl) -1-alkyl-2,2-dichloro-cyclopropanecarboxamides of the formulas (Ia) and (Ib)<chemistry id="chem0001" num="0001"><img file="EP0341475B1_D0001.tif" /></chemistry> in which<dl id="dl0001"><dt>X</dt><dd>represents hydrogen or chlorine,</dd></dl> found.

0005The invention relates both to the individual stereoisomers of the formulas (Ia) and (Ib) and to their mixtures.

0006The new compounds of the formulas (Ia) and (Ib) are obtained when - for the preparation of their mixtures in a first stage - Mixtures of (1R) - and (1S) -1-alkyl-2,2-dichloro-cyclopropanecarboxylic acid chlorides of the formulas (IIa) and (IIb)<chemistry id="chem0002" num="0002"><img file="EP0341475B1_D0002.tif" /></chemistry> with (R) -1-arylethylamines of the formula (III)<chemistry id="chem0003" num="0003"><img file="EP0341475B1_D0003.tif" /></chemistry> in which<dl id="dl0002"><dt>X</dt><dd>has the meaning given above,</dd></dl> if appropriate in the presence of an acid acceptor and if appropriate in the presence of a diluent and if appropriate for the preparation of the individual stereoisomers of the formulas (Ia) and (Ib) - separates the diastereomer mixtures obtained from the compounds of the formulas (Ia) and (Ib) in a second stage due to the different physical properties by customary methods.

0007The new stereoisomers of N- (R) - (1-aryl-ethyl) -1-alkyl-2,2-dichloro-cyclopropanecarboxamides of the formulas (Ia) and (Ib) and their mixtures are notable for strong action against fungi.

0008Surprisingly, the new stereoisomers of the formulas (Ia) and (Ib), in particular those of the formula (Ia), and also the mixtures of the compounds of the formulas (Ia) and (Ib), inter alia, have a considerably stronger fungicidal action than the known mixture of isomers of N- (1- (4-chlorophenyl) ethyl) -2,2-dichloro-1-ethyl-3-methylcyclopropanecarboxamide.

0009The invention preferably relates to the stereoisomers of the formula (Ia) and mixtures of the stereoisomers of the formulas (Ia) and (Ib) which contain at least 50% of the stereoisomers of the formula (Ia).

0010If you use a 1: 1 mixture of (1R) - and (1S) -2,2-dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarboxylic acid chloride (nomenclature see Beilstein) and (R) -1-phenylethylamine as Starting materials, the course of the reaction in the first stage of the process according to the invention can be represented by the following formula:<chemistry id="chem0004" num="0004"><img file="EP0341475B1_D0004.tif" /></chemistry> The 1-alkyl-2,2-dichloro-cyclopropanecarboxylic acid chlorides to be used as starting materials in the process according to the invention for the preparation of compounds of the formulas (Ia) and (Ib) are defined by the formulas (IIa) and (IIb). These are the compounds (1R) - and (1S) -2,2-dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarboxylic acid chloride.

00111: 1 mixtures of compounds of the formulas (IIa) and (IIb) are obtained if corresponding mixtures of (1R) - and (1S) -1-alkyl-2,2-dichloro-cyclopropanecarboxylic acids of the formulas (IIIa) and (IIIb)<chemistry id="chem0005" num="0005"><img file="EP0341475B1_D0005.tif" /></chemistry> with a chlorinating agent, such as. B. thionyl chloride, optionally in the presence of a catalyst such as. B. dimethylformamide, and optionally in the presence of a diluent, such as. B. methylene chloride, at temperatures between 10 ° C and 50 ° C.

0012The 1-alkyl-2,2-dichlorocyclopropanecarboxylic acids required as starting materials are defined by the formulas (IIIa) and (IIIb). These are the compounds (1R) - and (1S) -2,2-dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarboxylic acid.

00131: 1 mixtures of compounds of the formulas (IIIa) and (IIIb) are obtained if corresponding mixtures of (1R) - and (1S) -1-alkyl-2,2-dichloro-cyclopropanecarboxylic acid esters of the formulas (IVa) and (IVb)<chemistry id="chem0006" num="0006"><img file="EP0341475B1_D0006.tif" /></chemistry> in which<dl id="dl0003"><dt>R</dt><dd>represents alkyl, preferably methyl or ethyl,</dd></dl> with an aqueous alkali, such as. B. sodium hydroxide solution, optionally in the presence of an organic solvent, such as. As methanol or ethanol, at temperatures between 20 ° C and 100 ° C and then with a strong acid, such as. B. hydrochloric acid.

0014The 1-alkyl-2,2-dichlorocyclopropanecarboxylic acid esters required as starting materials are generally defined by the formulas (IVa) and (IVb).

0015Examples of the starting materials of the formulas (IVa) and (IVb) are: (1R) - and (1S) -2,2-dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarboxylic acid methyl ester and ethyl ester.

00161: 1 mixtures of compounds of the formulas (IVa) and (IVb) are obtained if alkenecarboxylic acid esters of the formula (V)<chemistry id="chem0007" num="0007"><img file="EP0341475B1_D0007.tif" /></chemistry> in which<dl id="dl0004"><dt>R</dt><dd>has the meaning given above,</dd></dl> with dichlorocarbene, which is optionally in situ, for example from chloroform and a strong base, such as. B. sodium hydroxide or potassium hydroxide, optionally in the presence of diluents, such as. As chloroform and water, and optionally in the presence of a phase transfer catalyst, such as. B. tetrabutylammonium bromide, at temperatures between 10 ° C and 60 ° C.

0017The starting materials of the formula (V) are already known (cf. J. Organomet. Chem. 96 (1975), 163-168).

0018Formula (III) defines the (R) -1-arylethylamines to be used further as starting materials in the process according to the invention for the preparation of compounds of the formulas (Ia) and (Ib).

0019It is (R) -1-phenylethylamine and (R) -1- (4-chlorophenyl) ethylamine.

0020The starting materials of the formula (777) are already known (cf. Indian J. Chem. 13 (1975), 631).

0021The first step of the process according to the invention for the preparation of the new stereoisomers of the formula (I) is preferably carried out using diluents. Practically all inert organic solvents can be used as diluents. These preferably include aliphatic and aromatic, optionally halogenated hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, ethers such as diethyl and Dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, ketones such as acetone, methyl ethyl, methyl isopropyl and methyl isobutyl ketone, Esters such as methyl acetate and ethyl ester, nitriles such as. B. acetonitrile and propionitrile, amides such as. B. dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone and dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric triamide.

0022Acid acceptors which can be used in the first stage of the process according to the invention are all acid binders which can customarily be used for such reactions. Alkali metal hydroxides such as, for. B. sodium and potassium hydroxide, alkaline earth metal hydroxides such. B. Calcium hydroxide, alkali carbonates and alcoholates such as sodium and potassium carbonate, sodium and potassium tert-butoxide, furthermore aliphatic, aromatic or heterocyclic amines, for example triethylamine, trimethylamine, dimethylaniline, dimethylbenzylamine, pyridine, 1,5-diazabicyclo- [4.3 , 0] -non-5-ene (DBN), 1,8-diazabicyclo- [5,4,0] -undec-7-ene (DBU) and 1,4-diazabicyclo- [2,2,2] - octane (DABCO).

0023The reaction temperatures can be varied within a substantial range in the first stage of the process according to the invention. In general, temperatures between -20 ° C and +80 ° C, preferably at temperatures between 0 ° C and 50 ° C.

0024The process according to the invention is generally carried out in the first stage at normal pressure.

0025To carry out the first stage of the process according to the invention, the starting materials required in each case are generally used in approximately equimolar amounts. However, it is also possible to use one of the two components used in each case in a larger excess. The reactions are generally carried out in a suitable diluent in the presence of an acid acceptor, and the reaction mixture is stirred for several hours at the temperature required in each case. Working up takes place after the first stage of the process according to the invention by customary methods.

0026In general, the procedure is such that the reaction mixture - if appropriate after concentration - with water and a water-immiscible organic solvent, such as. B. methylene chloride, shakes the organic phase with an aqueous mineral acid, such as. B. hydrochloric acid, washes, dries, filtered, the filtrate is concentrated, the residue by trituration with a suitable solvent, such as. B. cyclohexane, brings to crystallization and suction.

0027In the second stage, the separation of the diastereomers (Ia) and (Ib) can be carried out according to the methods suitable for such purposes. B, by fractional crystallization or with the help of chromatographic methods.

0028It is particularly preferred to use column chromatography separation processes, such as. B. the high pressure filtration over a silica gel column with an elution mixture of hexane, cyclohexane, methyl tert-butyl ether, heptane, carbon tetrachloride and / or propionitrile.

0029The active compounds according to the invention have a strong biological action and can be used practically as fungicides for combating fungi.

0030Fungicidal agents in crop protection are used to control Plasmodiophoromycetes, Oomycetes, Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes, Deuteromycetes.

0031Some pathogens of fungal diseases that fall under the generic names listed above may be mentioned as examples, but not by way of limitation: Pythium species, such as, for example, Pythium ultimum; Phytophthora species, such as, for example, Phytophthora infestans; Pseudoperonospora species, such as, for example, Pseudoperonospora humuli or Pseudoperonospora cubensis; Plasmopara species, such as, for example, Plasmopara viticola; Peronospora species, such as, for example, Peronospora pisi or P. brassicae; Erysiphe species, such as, for example, Erysiphe graminis; Sphaerotheca species, such as, for example, Sphaerotheca fuliginea; Podosphaera species, such as, for example, Podosphaera leucotricha; Venturia species, such as, for example, Venturia inaequalis; Pyrenophora species, such as, for example, Pyrenophora teres or P. graminea (Conidial form: Drechslera, Syn: Helminthosporium); Cochliobolus species, such as, for example, Cochliobolus sativus (Conidial form: Drechslera, Syn: Helminthosporium); Uromyces species, such as, for example, Uromyces appendiculatus; Puccinia species, such as, for example, Puccinia recondita; Tilletia species, such as, for example, Tilletia caries; Ustilago species, such as, for example, Ustilago nuda or Ustilago avenae; Pellicularia species, such as, for example, Pellicularia sasakii; Pyricularia species, such as, for example, Pyricularia oryzae; Fusarium species, such as, for example, Fusarium culmorum; Botrytis species, such as, for example, Botrytis cinerea; Septoria species, such as, for example, Septoria nodorum; Leptosphaeria species, such as, for example, Leptosphaeria nodorum; Cercospora species, such as, for example, Cercospora canescens; Alternaria species, such as, for example, Alternaria brassicae; Pseudocercosporella species, such as, for example, Pseudocercosporella herpotrichoides.

0032The fact that the active compounds are well tolerated by plants in the concentrations required to combat plant diseases enables treatment of above-ground parts of plants, of propagation stock and seeds, and of the soil.

0033The active compounds according to the invention are particularly suitable for controlling Pyricularia oryzae on rice.

0034Depending on their respective physical and / or chemical properties, the active ingredients can be converted into customary formulations, such as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, very fine encapsulations in polymeric substances and in coating compositions for seeds, and ULV Cold and warm mist formulations.

0035These formulations are prepared in a known manner, for example by mixing the active ingredients with extenders, that is to say liquid solvents, pressurized liquefied gases and / or solid carriers, optionally using surface-active agents, that is to say emulsifiers and / or dispersants and / or foam-generating agents. In the case of the use of water as an extender, for example organic solvents can also be used as auxiliary solvents. The following are essentially suitable as liquid solvents: aromatics, such as xylene, toluene, or alkylnaphthalenes, chlorinated aromatics or chlorinated aliphatic hydrocarbons, such as chlorobenzenes, chlorethylenes or methylene chloride, aliphatic hydrocarbons, such as cyclohexane or paraffins, for example Petroleum fractions, alcohols, such as butanol or glycol, and their ethers and esters, ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents, such as dimethylformamide and dimethyl sulfoxide, and water; Liquefied gaseous extenders or carriers mean liquids which are gaseous at normal temperature and under normal pressure, for example Aerosol propellants, such as halogenated hydrocarbons and butane, propane, nitrogen and carbon dioxide; The following are suitable as solid carriers: for example natural rock powder, such as kaolins, alumina, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth and synthetic rock powder, such as highly disperse silica, aluminum oxide and silicates; as solid carriers for granules come into question: for example broken and fractionated natural rocks such as calcite, marble, pumice, sepiolite, dolomite and synthetic granules from inorganic and organic flours and granules from organic material such as sawdust, coconut shells, corn cobs and tobacco stalks; Possible emulsifiers and / or foam-generating agents are: for example nonionic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, for example Alkylaryl polyglycol ethers, alkyl sulfonates, alkyl sulfates, aryl sulfonates and protein hydrolyzates; Possible dispersing agents are, for example, lignin sulfite waste liquor and methyl cellulose.

0036Adhesives such as carboxymethyl cellulose, natural and synthetic polymers in the form of powders, granules or latices, such as gum arabic, polyvinyl alcohol, polyvinyl acetate, and also natural phospholipids, such as cephalins and lecithins, and synthetic phospholipids can be used in the formulations. Other additives can be mineral and vegetable oils.

0037Dyes such as inorganic pigments, for example iron oxide, titanium oxide, ferrocyan blue and organic dyes such as alizarin, azo and metal phthalocyanine dyes and trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc can be used.

0038The formulations generally contain between 0.1 and 95 percent by weight of active compound, preferably between 0.5 and 90%.

0039The active compounds according to the invention can be present in the formulations in a mixture with other known active compounds, such as fungicides, insecticides, acaricides and herbicides, and also in mixtures with fertilizers and growth regulators.

0040The active ingredients can be used as such, in the form of their formulations or the use forms prepared therefrom, such as ready-to-use solutions, suspensions, wettable powders, pastes, soluble powders, dusts and granules. They are used in the customary manner, for example by watering, spraying, atomizing, scattering, dusting, foaming, brushing, etc. It is also possible to apply the active ingredients using the ultra-low-volume method or to inject the active ingredient preparation or the active ingredient itself into the soil. The seeds of the plants can also be treated.

0041When treating parts of plants, the active compound concentrations in the use forms can be varied within a substantial range. They are generally between 1 and 0.0001% by weight, preferably between 0.5 and 0.001%.

0042In the seed treatment, amounts of active ingredient of 0.001 to 50 g per kilogram of seed, preferably 0.01 to 10 g, are generally required.

0043When treating the soil, active ingredient concentrations of 0.00001 to 0.1% by weight, preferably 0.0001 to 0.02%, are required at the site of action.

Manufacturing examples

example 1

0044<chemistry id="chem0008" num="0008"><img file="EP0341475B1_D0008.tif" /></chemistry> 9.5 g (44 mmol) of a 1: 1 mixture of (1R) - and (1S) -2,2-dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarboxylic acid chloride become a mixture with stirring and ice cooling 6.2 g (40 mmol) of (R) -1- (4-chlorophenyl) ethylamine, 4.8 g (48 mmol) of triethylamine and 40 ml of methylene chloride. The reaction mixture is then stirred at 20 ° C. for 4 hours, diluted with water and methylene chloride and shaken. The organic phase is separated off, washed with 2N hydrochloric acid, dried with magnesium sulfate and filtered. The solvent is distilled off from the filtrate in a water jet vacuum, the product remaining in the residue is brought to crystallization by trituration with cyclohexane and isolated by suction.

004513.8 g (98% of theory) of a diastereomer mixture (1a / 1b) of N- (R) - (1- (4-chlorophenyl) ethyl) -2,2-dichloro-1-ethyl- 3t-methyl-1r-cyclopropanecarboxylic acid amide with a melting point of 144 ° C - 146 ° C. [α]<maths id="math0001"><math display="inline"><mrow><mfrac linethickness="0"><mrow><mtext>25</mtext></mrow><mrow><mtext>D </mtext></mrow></mfrac></mrow></math><img file="EP0341475B1_D0009.tif" /></maths> : + 40.92 (CHCl₃, c = 5.1).

004610th g (30 mmol) of the diastereomer mixture are separated by means of HPLC (high performance liquid chromatography / high resolution liquid chromatography) on a silica gel column (Merck, 5 - 20 μ grain size) with the eluent mixture heptane / methyl tert-butyl ether (85:15).

00474.1 g of N- (R) - (1- (4-chlorophenyl) ethyl) - (1R) -2,2-dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarboxamide ( 1b) eluted from the melting point 158 ​​° C. [α]<maths id="math0002"><math display="inline"><mrow><mfrac linethickness="0"><mrow><mtext>25</mtext></mrow><mrow><mtext>D </mtext></mrow></mfrac></mrow></math><img file="EP0341475B1_D0010.tif" /></maths> : + 20.05 (CHCl₃, c = 2.00).

0048The second fraction obtained is 4.4 g of N- (R) - (1- (4-chlorophenyl) ethyl) - (1S) -2,2-dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarboxamide (1a ) melting point 154 ° C. [α]<maths id="math0003"><math display="inline"><mrow><mfrac linethickness="0"><mrow><mtext>25</mtext></mrow><mrow><mtext>D </mtext></mrow></mfrac></mrow></math><img file="EP0341475B1_D0011.tif" /></maths> : + 61.01 (CHCl₃, c = 2.03).

0049The compounds listed below can be obtained analogously to Example 1.

Example 2

0050<chemistry id="chem0009" num="0009"><img file="EP0341475B1_D0012.tif" /></chemistry>

Starting materials of formulas (IIa) and (IIb)

0051<chemistry id="chem0010" num="0010"><img file="EP0341475B1_D0013.tif" /></chemistry> 29 g (0.15 mol) of a 1: 1 mixture of (1R) - and (1S) -2,2-dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarboxylic acid (IIIa / IIIb) in 30 ml Dissolved methylene chloride. Then 2 drops of dimethylformamide and then 28.6 g (0.24 mol) of thionyl chloride are added dropwise with stirring and the mixture is heated to boiling under reflux for a further 30 minutes. It is then worked up by distillation in a water jet vacuum.

005225 g (78% of theory) of a 1: 1 mixture of (1R) - and (1S) -2,2-dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarboxylic acid chloride with a boiling point of 80 ° C.-85 are obtained ° C (15 Torr / 2 kPa).

Starting materials of the formulas (IIIa) and (IIIb)

0053<chemistry id="chem0011" num="0011"><img file="EP0341475B1_D0014.tif" /></chemistry> A solution of 67 g (1.675 mol) of sodium hydroxide in 80 ml of water becomes a solution of 185 g (0.82 mol) of a 1: 1 mixture of (1R) - and (1S) -2,2-dichloro-1 -ethyl-3t-methyl-1r-cyclopropanecarboxylic acid ethyl ester in 400 ml of ethanol and the reaction mixture is stirred at 80 ° C for 3 hours. The ethanol is then largely distilled off in a water jet vacuum, the residue is diluted with water and acidified with 10% hydrochloric acid. The mixture is then extracted with methylene chloride, the organic phase is concentrated, the residue is crystallized by trituration with petroleum ether and the product is isolated by suction.

0054108 g (67% of theory) of a 1: 1 mixture of (1R) - and (1S) -2,2-dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarboxylic acid with a melting point of 77 ° C.-79 are obtained ° C.

Starting materials of formulas (IVa) and (IVb)

0055<chemistry id="chem0012" num="0012"><img file="EP0341475B1_D0015.tif" /></chemistry> A solution of 405 g (6.4 mol) of 88% potassium hydroxide in 307 ml of water and 8.3 g (0.026 mol) of tetrabutylammonium bromide become a solution of 181 g (1.28 mol) * E-2-ethyl-2 -butensäureethylester in 550 ml of chloroform and the reaction mixture is stirred vigorously at 40 ° C for 20 hours. The organic phase is then separated off, washed with 1N hydrochloric acid and distilled in a water jet vacuum. * Nomenclature (E / Z) vg. J. Am. Chem. Soc. 90: 509-510 (1968).

0056185 g (64% of theory) of a 1: 1 mixture of (1R) - and (1S) -2,2-dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarboxylic acid ethyl ester with a boiling point of 95 ° C.-102 are obtained ° C (15 Torr / 2kPa).

Starting materials of the formula (III)

0057<chemistry id="chem0013" num="0013"><img file="EP0341475B1_D0016.tif" /></chemistry> The solutions heated to approx. 60 ° C - 70 ° C of 91 g (0.587 mol) rac. p-Chlorophenethylamine in 300 ml of ethanol and 122 g of (S) - (-) - N-phenylcarbamate lactic acid in 800 ml of ethanol are combined and left to stand overnight. The crystal slurry is filtered off (93 g) and treated with 200 ml of 10% sodium hydroxide solution / 300 ml of methylene chloride. The organic phase is washed with water, dried over magnesium sulfate and evaporated.

005844.5 g (+) - enantiomer with an optical purity of 89.4% ee (enantiomeric excess) are obtained.

005944 g (0.28 mol) of this amine are dissolved in 150 ml of ethanol, heated to 60 ° C. and with a solution of 59 g (0.28 mol) (S) - (-) - N-, which is also heated to 60 ° C. Phenylcarbamate lactic acid combined in 400 ml of ethanol. The slowly crystallizing salt is suctioned off after standing overnight (74 g) and, as previously described, broken down again with 300 ml of methylene chloride / 10% sodium hydroxide solution.

0060After washing, drying and concentrating the organic phase, 40.4 g (88.8% of theory) (+) - enantiomer with an optical purity of 97.4% ee (enantiomeric excess) are obtained.

Usage example

Pyricularia test (rice) / protective

0061Solvent: 12.5 parts by weight of acetone Emulsifier: 0.3 part by weight of alkylaryl polyglycol ether To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent and the concentrate is diluted to the desired concentration with water and the stated amount of emulsifier.

0062To test for protective effectiveness, young rice plants are sprayed with the preparation of active compound to runoff. After the spray coating has dried, the plants are inoculated with an aqueous spore suspension of Pyricularia oryzae. The plants are then in a greenhouse at 100% rel. Humidity and 25 ° C.

00634th The disease infestation is evaluated days after the inoculation.

0064The compound of formula (1a) according to the invention shows a clear superiority in effectiveness compared to the prior art in this test.<tables id="tabl0001" num="0001"><img file="EP0341475B1_D0017.tif" /></tables>