CS216541B2 - Ectoparazitocide means and method of making the active substances - Google Patents

Description

The novel compound of formula (Ia) above may be obtained by (E) isomer of (+) -trans-3- [2-chloro-2- (4-chlorophenyl) vinyl] cyclopropane-1-carboxylic acid chloride of formula IIa.

is reacted with 3-phenoxy-4-fluorobenzaldehyde of formula III

in the presence of at least an equimolar amount of alkali metal cyanide, optionally in the presence of a catalyst, optionally using diluents, at a temperature between 0 and 100 ° C.

In our related Czechoslovak patent specification 216 539, an ectoparasiticidal composition is disclosed which contains as active ingredient a mixture of the E- and Z-isomers of the (+) - (α-cyano-3-phenoxy-4-fluorobenzyl) ester of the (+) -tirans- 3- [2-chloro-2- (4-chlorophenyl) vinyl] -2,2-dimethylcyclopropane-1-carboxylic acid and a process for the preparation of this mixture of isomers. It will be understood that the individual E-isomer of the present invention can also be obtained by the art-known resolution of the aforementioned mixture of E, Z-isomers into individual antipodes.

The novel compound of formula Ia is characterized by high insecticidal and acaricidal activity.

Surprisingly, the novel compound according to the invention exhibits considerably higher insecticidal and acaricidal, in particular ectoparasiticidal, activity than the known mixtures of the isomers of ([-cyan-3-phenoxy-4-fluorobenzyl) 3- [2-chloro-2- (4) -isomer]. (chlorophenyl) vinyl] -2,2-dimethylcyclopropane-1-carboxylic acid.

The acid chloride of the above formula IIIa used as starting material is not yet described in the literature. This compound can be obtained by the E-isomer of (+) -trans-3- [2-chloro-2- (4-chlorophenyl) vinyl) -2,2-diinethylcyclopropane-1-carboxylic acid of formula IVa

It is reacted with a chlorinating agent, for example with thionyl chloride, optionally in the presence of a diluent, for example carbon tetrachloride, at a temperature between 10 and 100 ° C.

The acid of formula IVa is not yet described in the literature.

This acid can be obtained by dividing) +) -trans-3- (E, Z-2-chloro-2- (4-chlorophenyl) vinyl] -2,2-dimethylcyclopropane-1-carboxylic acid into individual E- and Z- isomers.

(+) -trans-3- [E, Z-2-chloro-2- (4-chlorophenyl) vinyl] -2,2-dimethylcyclopropane-1-carboxylic acid of formula IV is obtained by reacting the corresponding alkyl ester of formula

R is C 1 -C 4 alkyl, saponified in a conventional manner, for example by heating the above ester with an alkaline lye, for example aqueous sodium alcoholic lye, to a temperature between 50 ° C and 10 ° C.

To work up the reaction mixture, the alcohol is optionally distilled off, the product is extracted with a water-immiscible solvent such as methylene chloride, and the extractant is distilled off under reduced pressure.

Examples of esters of formula V are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl (+) -trans-3- [E, Z-2- chloro-2- (4-chlorophenyl) vinyl] cyclopropane-1-carboxylic acid.

Esters of formula (V) are not yet described in the literature. These compounds are obtained by: (+) - trans-3-formyl-2,2-dimethylcyclopropane-1-carboxylic acid ester of formula VI,

QHC,

CH-, .N

H

Ao-OR

CH, (Knows) in which

R is C 1 -C 4 alkyl, reacted with a 4-chloro-α-chlorobenzylphosphonic ester of formula VII,

/ i ^Z

Whose

Vil) in which

R represents a (C 1 -C 4) alkyl group in the presence of a base, for example sodium methoxide, optionally in the presence of a diluent, for example ethanol and / or tetrahydrofuran, at a temperature between -10 and +50 ° C.

For work-up, the reaction mixture is diluted with water and extracted with a water-immiscible solvent such as methylene chloride ¹ . The extracts were dried, filtered and the solvent was distilled off under reduced pressure.

Esters of the above general formula

VIs are already known (see DOS No. 2,615,160). Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl (+) -trans-3-formyl-2,2-dimethylcyclilopropane-1-carboxylic acid tert-butyl ester .

The 4-chloro-α-chlorobenzylphosphonic acid esters of formula VII above are prepared from the known 4-chlorobenzaldehyde according to the following reaction scheme:

OH

(here

Reaction of 4-chlorobenzaldehyde with phosphorous acid esters, for example diethyl phosphite, optionally in the presence of a catalyst such as triethylamine, at a temperature between 20 and 100 ° C, gives the esters

4-chloro-N-hydroxybenzylphosphonic acid of formula VIII above. These esters can be converted to 4-chloro-α-chlorobenzylphosphonic acid esters of formula VII by reaction with chlorinating agents, for example thionyl chloride, at a temperature between 20 and 100 ° C.

Examples of compounds of formula (VII) include 4-chloro-α-chlorobenzylphosphonic acid dimethyl ester, diethyl ester, diisopropyl ester and di-sec-butyl ester.

The mixture of ε, Ζ-isomers of (+) -trans-3- [2-chloro-2- (4-chlorophenyl) vinyl] -2,2-dimethylcyclopropane-1-carboxylic acid can be separated by dividing the mixture of ε, The Ζ-isomers of this acid are dissolved in a water-immiscible solvent such as methylene chloride by adding 0.001 to 1, preferably 0.1 to 1 equivalent of a base, such as aqueous sodium hydroxide, in X degrees, wherein X is a number between 1 and oo, where oo is a continuous process, preferably 2 to 100, is converted to a salt, each time the base is added, the salt is extracted with water in X stages, the individual aqueous fractions are acidified with a mineral acid such as hydrochloric acid, extracted with a solvent immiscible with water, such as methylene chloride, each individual extract is worked up in the usual manner, for example by drying, filtering and distilling off the solvent and the fraction in which one of the E or Z isomers predominates (according to N analysis). By MR spectroscopy], they are recrystallized from an organic solvent, preferably a hydrocarbon containing from 5 to 10 carbon atoms.

The mixture of the ε, Ζ-isomers of (+) - tr, ans-3- [2'-chloro-2- (4-chlorophenyl) vinyl] -2,2-dimethylmethylcyclopropane-1-carboxylic acid can also be separated by: The mixture of ε, Ζ-isomers of this acid is dissolved in an aqueous alkaline liquor, for example sodium hydroxide, which contains exactly one equivalent of base, by adding 0.001 to 1, preferably 0.1 to 1 equivalent of mineral acid in X degrees, wherein X is a value of between 1 and where oo is a continuous process, preferably between 2 and 100, the acid is recovered, after each addition of acid, extraction is performed with a water-immiscible organic solvent, for example methylene chloride, each individual extract being treated in the usual manner, for example drying, filtering and distilling off the solvent, and a fraction in which one of the E or Z isomers predominates (according to NMR analysis, they are recrystallized from an organic solvent, preferably from a hydrocarbon containing his 5-10 · carbon atoms.

The 3-phenoxy-4-fluorobenzaldehyde of the formula III, which is used as starting material in the preparation of the novel compound of the formula Ia, is already known (see DOS No. 2 709 264).

As alkali metal cyanides, which are used to prepare the novel compound of formula

Preferably, sodium cyanide and potassium cyanide are mentioned.

218541

The process for preparing the novel compound of formula (Ia) is preferably carried out using diluents. Suitable diluents are virtually all inert organic solvents, which include, in particular, aliphatic and aromatic and / or chlorinated hydrocarbons, such as pentane, hexane, heptane, cyclohexane, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-. dichlorobenzene, ethers such as diethyl ether, dibutyl ether, tetrahydrofuran and dioxane, ketones such as acetone, methyl ethyl ketone, methylisopropyl ketone and methyl isobutyl ketone, as well as nitriles such as acetonitrile and propionitrile.

Preferably, of the above-mentioned solvents, water-immiscible solvents are used in combination with water as the second component of the solvent system, i.e. the process is carried out in a two-phase system.

In the present case, the catalysts which are usually used in phase-to-phase reactions can be used as auxiliary agents for the phase transfer of the reactants. In particular, tetraalkyl- and trialkylaralkylammonium salts such as tetrabutylammonium bromide, methyltrioctylammonium chloride and trimethylbenzylammonium hydrogen sulphate may be mentioned.

The reaction temperature is generally kept between 0 and 100 ^Q C, preferably between 10 and 50 ° C. The reaction is usually carried out under normal pressure.

To work according to the process of the invention, the starting materials are usually employed in equimolar amounts. The excess of some of the reaction components does not bring any significant advantages. The reaction is generally carried out in suitable solvents, optionally in the presence of a catalyst. The reaction mixture is stirred for several hours at the desired temperature, then an organic solvent such as toluene is added and the organic phase is worked up in the usual manner by washing, drying and distilling off the solvent.

The new compound according to the invention results in an oily form and cannot be distilled without decomposition, but is purified by so-called "distillation", i.e. by prolonged heating under reduced pressure to moderate elevated temperature to remove the last residual volatiles. ¹ H-NMR spectrum was used for characterization.

The active compound according to the invention exhibits, at low toxicity, a warm-blooded and rapidly progressing ectoparasiticidal (insecticidal and acaricidal effect, in particular against mites which attack domestic animals such as cattle, sheep and rabbits as animal ectoparasites. animal ectoparasites from the mite order (Acarin J.

The active compound according to the invention can be converted into the customary formulations such as solutions, emulsions, wettable powders, suspensions, powders, dusts, foams, pastes, soluble powders, granules, aerosols, concentrates based on suspensions and emulsions, powdered, seed diluents, natural and synthetic substances impregnated with active substances and encapsulated forms in polymeric substances.

These compositions are prepared in a known manner, for example by mixing the active ingredient with fillers, i.e. liquid solvents, with liquefied gases under pressure and / or solid carriers, optionally using surfactants, i.e. emulsifiers and / or dispersants and / or foaming agents. If water is used as a filler, it is also possible to use, for example, organic solvents as co-solvents. Basically suitable liquid solvents are: 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, as well as their ethers and esters, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or. cyclohexanone, strongly polar solvents such as dimethylformamide and dimethylsulfoxide as well as water. By liquefied gaseous fillers or carriers is meant those liquids which are gaseous at normal temperature and pressure, for example aerosol propellants such as halogenated hydrocarbons as well as butane, propane, nitrogen and carbon dioxide. Suitable solid carriers are: natural stone meal, such as kaolins, alumina, talc, chalk, quartz, attapulgite, montrnorillonite or diatomaceous earth, and synthetic stone meal such as. highly disperse silicic acid, alumina and silicates. Suitable solid carriers for the preparation of granulates are crushed and fractionated natural stone materials such as limestone, marble, pumice, sepiolite and dolomite, as well as synthetic granules of inorganic and organic flours and granules of organic material such as sawdust, coconut shells. nuts, corn sticks and tobacco stems. Suitable emulsifiers and / or foaming agents are nonionic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, polyalkoxyethylene ethers of fatty alcohols, e.g. .

The compositions of the invention may include adhesives such as carboxymethylcellulose, natural and synthetic powdered, granular or latex polymers such as gum arabic, polyvinyl alcohol and polyvinyl acetate.

Further, these compositions may contain coloring agents such as inorganic pigments, for example iron oxide, titanium dioxide and ferrocyanide blue, and organic dyes such as alizarin dyes and metallic azo.

phthalocyanine dyes as well as trace elements such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.

The concentrates generally contain between 0.1 and 95% by weight, preferably between 0.5 and 90% by weight of active ingredient.

The active compound according to the invention can be used in the form of commercial preparations and / or in dosage forms prepared from these preparations.

The content of active ingredient in dosage forms prepared from commercial preparations can vary within wide limits. The concentration of the active ingredient in the dosage forms can range from 0.0000001 to 100 weight percent, preferably from 0.0001 to 10 P / w.

The application is carried out in a conventional manner adapted to the application form used.

The compositions according to the invention are prepared in a manner known per se by mixing the individual components in the necessary weight ratios, the order of addition of the active and auxiliary substances generally not playing any significant role.

In the veterinary field, the active ingredient according to the invention is applied in a manner known per se, such as orally in the form of, for example, tablets, capsules, beverages or granules, dermally in the form of for example dipping, spraying, pour-on and spot-onj powders, as well as parenterally in the form of, for example, injections.

Example 1

Test for Boophilus microplus (strain Biarra, organophosphate resistant) solvent:

weight of ethylene glycol monomethyl ether emulsifier:

parts by weight of nonylphenol polyglycol ether

To prepare a suitable composition, 3 parts by weight of the active ingredient are mixed with 7 parts of the above solvent / emulsifier mixture, and the emulsifiable concentrate obtained is diluted with water to the desired concentration.

The fully prepared adult ticks of Boophilus microplus (resistant J.) are immersed in the above active ingredient for 1 minute. After immersing 10 ticks each, the treated specimens are transferred to petri dishes, the bottom of which is covered with filter paper of the appropriate size.

After 10 days, the efficacy of the composition is determined by detecting egg clutch suppression over untreated control ticks. The observed effect is expressed in%, with 100% indicating that no egg has been deposited, and 0% means that the ticks lay eggs in the normal amount.

The active compounds tested, the active compound concentrations and the results obtained are shown in the following table.

Table

Test for Boophilus microplus (Biarra strain, organophosphate resistant)

active substance (example no.) active substance concentration (PPm) egg suppression effect (%) 10 000 100 ALIGN! 3 000 100 ALIGN! 1 1 000 100 ALIGN! 300 100 ALIGN! 100 ALIGN! > 50 30 > 50 10 <50 3 0 Preparation of active substances according to the invention tetrabutylammonium bromide. Reaction

The following examples illustrate the invention without limiting it in any way.

Example 1

1.08 g (0.005 mol) of 3-phenoxy-4-fluorobenzaldehyde, and 1.52 g (0.005 mol) of (+) - trans-3- [E-2-chloro-2- (4-chlorophenyl) vinyl] chloride 1,2-Dimethylcyclopropanecarboxylic acid was added dropwise to a mixture of 0.4 g of sodium cyanide, 0.6 ml of water, 20 ml of n-hexane and 0.1 g of the mixture while stirring at 20-25 ° C. After stirring at 20-25 ° C for 4 hours, 100 ml of toluene are added and the mixture is shaken twice with 60 ml of water each time, the organic phase is separated, dried over sodium sulphate and the solvent is distilled off under water pump vacuum. the solvents were removed by brief distillation at 60 ° C at 1 mm Hg to give (+ 1 - (ω-cyano-3-phenoxy-4-fluorobenzyl) ester (+) - trans-3- [E-2-chloro- 2- (4-chlorophenyl) vinyl] -2,2-dimethylcyclopropanecarboxylic acid of formula

1 H-NMR spectrum (deuterochloroform / tetramethylsilane, τ values in ppm): aromatic protons:

2.3 to 3.1 (multiplet, 12 H), proton of the benzyl residue:

3.70 (singlet, 1/2 H) and 3.72 (singlet,

1/2 H), vinyl residue proton:

4.16 to 4.40 (multiplet, 1H), cyclopropane residue protons:

7.64 to 8.07 (multiplet, 1H) and 8.39 (doublet, 1H), protons of the dimethyl group:

8.57 to 8.92 (multiplet, 6H).

The following examples describe the preparation of starting materials.

Example A 1

Dissolve 1.0 g (0.0035 mol) of (+) - trans-3- [E-2-chloro-2- (4-chlorophenyl) vinyl] -2,2-dimethylcyclopropanecarboxylic acid in 20 ml of tetramethane and 5 ml of thionyl chloride is slowly added dropwise at 25 DEG C. The reaction mixture is refluxed for a further 4 hours, after which excess thionyl chloride and carbon tetrachloride are distilled off under a water pump vacuum. bath temperature 60 ° C.

(+) -Trans-3- [E-2-chloro-2- (4-chlorophenyl) vinyl] -2,2-dimethylcyclopropanecarboxylic acid chloride was obtained as an oily liquid. The product corresponds to the formula

22.2 g (0.071 mol) of (+) -trans-3- [E, Z-2-chloro-2- (4-chlorophenyl) vinyl] -2,2-dimethylcyclopropanecarboxylic acid ethyl ester are dissolved in 100 ml of ethanol, A solution of 5.7 g of sodium hydroxide in 100 ml of water was added and the mixture was heated under reflux for 4 hours with stirring. The ethanol was distilled off under a water pump vacuum, the residue was taken up in 300 ml of warm water and extracted once with 300 ml of methylene chloride. The aqueous phase is separated, acidified with concentrated hydrochloric acid and extracted twice with 300 ml of methylene chloride each time. The organic phase is separated, dried over magnesium sulphate and the solvent is distilled off under water pump vacuum. Last residues of solvent were removed by brief incipient distillation at a pressure of 267 Pa at a bath temperature of 60 ^Q C, yielding 15.5 g (76.6%) of (+) -trans-3- [E, Z-2-chloro-2- (4-chlorophenyl) vinyl] -2,2-dimethylcyclopropanecarboxylic acid in the form of a viscous oil, which crystallizes after some time and melts at 120-132 ° C after recrystallization from acetonitrile.

Example 1 A d

The ester of formula (V) used can be prepared as follows:

2.53 g (0.11 mol) of sodium are dissolved in portions in 50 ml of ethanol. After dissolution of all sodium, 150 ml of anhydrous tetrahydrofuran was added and 29.7 g (0.1 mol) of 4-chloro-α-chlorobenzylphosphonic acid diethyl ester dissolved in 30 ml of anhydrous tetrahydrofuran was added dropwise at 0 ° C with stirring. The mixture was stirred at 0-5 ° C for a further 2 hours. 17 g (0.1 mol) of (+) -trans-2,2-dlmethyl-3- ethyl ester were added dropwise with stirring at 0 ° C. formylcyclopropanicarboxylic acid dissolved in 30 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at 20-25 ° C for 12 hours, then 500 mL of water was added and the resulting mixture was extracted with ^CH 3 (2 x 300 mL of methylene chloride). The organic phase is separated, dried over magnesium sulphate, the solvent is distilled off under a water pump vacuum and the residue is subjected to vacuum distillation.

23.2 g (74.1% of theory) of (+) - trans-3- [E, Z-2-chloro-2- (4-chlorophenyl) vinyl] -2,2-dimethylcyclopropanecarboxylic acid ethyl ester are obtained. in the form of a yellow oil, boiling point 155 DEG-165 DEG C./0.1 mbar.

Example A 4

Ci r!

\ / CH, H

i. / / COOH

31.6 g (0.111 mol) of (+) - trans- [E, Z-2-chloro-2- (4-chlorophenyl) vinyl] -2,2-dimethylcyclopropanecarboxylic acid, with an E / Z isomer ratio of 60/40 Dissolve in 150 ml of methylene chloride and shake the solution with 0.885 g (0.022 mol) of sodium hydroxide in 50 ml of water. The aqueous phase is then separated. This procedure is repeated four more times. 5 fractions of an aqueous salt solution are obtained, which are each acidified separately with concentrated hydrochloric acid and extracted twice with 50 ml of methylene chloride each time. The organic phases are separated, dried over magnesium sulphate and the solvent is evaporated off under vacuum. Five fractions containing the above acid with different E and Z isomers are obtained. The E / Z ratio is determined by ¹ H-NMR spectrum.

Fraction I, ie first separated acid:

E / Z = 50/50;

Fraction V:

E / Z = 87/13.

Fraction V (5 g) was dissolved in cyclohexane at 30-40 ° C. After standing at ambient temperature crystallized (+) -trans-3- [E-2-chloro-2- (4-chlorophenyl) -vinyl-2,2-dimethylcyklopropainkarboxylová acid remains as colorless crystals of melting point 138-139 C. The structure of ^{Q 1} H-NMR spectrum.

¹ H-NMR spectrum (deuterochloroform / tetramethylsilane, τ values in ppm):

aromatic protons:

2.43 to 2.74 (multiplet, 4H), vinyl residue proton:

4.24 (doublet, 1H), cyclopropane residue protons:

7.74 to 8.04 (multiplet, 1H) and 8.39 (doublet,

1H), protons of dimethyl grouping:

8.73 (singlet, GH).

Claims (2)

Ectoparasiticidal composition, characterized in that (+) - (α-cyano-3-phenoxy-4-fluorobenzyl) ester (+) -trans-3- [E-2-chloro- 2- (4-chlorophenyl) vinyl] -2,2'-dimethylcyclopropanecarboxylic acid of formula Ia. A process for the preparation of (+) - (α-cyano-3-phenoxy-4-fluorobenzyl) (+) -trans-3- [E-2-chloro-2- (4-chlorophenyl) vinyl] -2,2-ester -dimethylcyclopropanecarboxylic acid of the above formula (Ia), characterized in that (+) - trans-3- [E-2-chloro-2- (4-chlorophenyl) vinyl] cyclopropane-1-carboxylic acid chloride of the formula IIa 'is reacted with 3-phenoxy-4-fluorobenzaldehyde in the presence of at least an equimolar amount of alkali metal cyanide, optionally in the presence of a catalyst and optionally using diluents, at a temperature between 0 and 100 ° C.