RU2051152C1 - Derivatives of 1,4-bis-substituted 2,6,7-trioxabicyclo-[2,2,2]-octanes - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: derivatives of 1,4-bis-substituted 2,6,7-trioxabicyclo-[2,2,2]-octanes of the formula (I) R-C(CH₂O)₃C-X (1), where R and X have corresponding meanings; LD₅₀ less than about 400 mg/kg flies, Musca domestica. Value LD₅₀ in the presence of synergist is less than about 60 mg/kg. Pesticide activity is found against broad class of different insects. Pesticide activity is strongly enhanced in the case of definite synergist types use. Synthesized compounds were used for insect demolition. EFFECT: improved method of synthesis. 5 cl, 4 tbl

Description

 The invention relates to a new class of pesticides, which are 1,4-bis-substituted-2,6,7-trioxabicyclo (2.2.2) octanes.

 The invention was developed with the support of the United States Government in accordance with document N ES00049 issued by the National Institute of Health. The United States Government has certain rights in this invention.

 Pesticides are chemicals that are used to attack various insects found on valuable agricultural plants, livestock, as well as people and their habitats. These chemicals include insecticides, fungicides, herbicides (or weed killers), nematicides, shellfish killers, acaricides and parasite killers.

 Currently, a large number of classes of compounds that have pesticidal activity are known, however, known pesticidal compositions may become less effective over time due to the fact that the resistance of those organisms for the destruction of which they are intended to increase. This leads to the fact that the constant development and development of new types of pesticides is necessary.

 An ideal pesticide should be highly effective in killing insects and biodegradable.

 The purpose of the invention is the development of pesticidal compounds with the desired properties.

In accordance with one aspect of the present invention, the pesticides contain a compound characterized by the formula RC (CH ₂ O) ₃ CX, where R and X have the above meanings, and this compound has pesticidal activity, since its 50% lethal dose LD ₅₀ expressed in micrograms, the compound per gram live weight of the Musca domestica flour (housefly) is not more than about 400.

In accordance with another aspect of the present invention, a compound characterized by the formula RC (CH ₂ O) ₃ CX, where R and X are as defined below, are in a synergistic composition to provide pesticidal activity and together they provide a 50% lethal dose of LD ₅₀ expressed in micrograms per gram of live weight, not exceeding about 60.

In accordance with another aspect of the present invention, the composition, as described above, contains a compound characterized by the formula RC (CH ₂ O) ₃ CX, where R is propyl, isopropyl, butyl, C ₃ -C ₁₀ cycloalkyl or phenyl, X C ₆ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ cycloalkenyl, C ₂ -C ₆ alkynyl or phenyl substituted with one or more substituents selected from a halogen atom, a cyano, azido or nitro group, or C ₁ - C ₂ -alkyl, optionally substituted with 1 to 3 halogen, provided that when X is 4-fluorophenyl, R is not phenyl.

In accordance with another aspect of the present invention, the composition, as described above, contains a compound characterized by the formula RC (CH ₂ O) ₃ CX, where X is 4-chlorophenyl and R is propyl, isopropyl, butyl, cyclopentyl, cyclohexyl or phenyl, or where X is cyclohexyl and R is cyclohexyl or phenyl, or where R is cyclohexyl and X is phenyl, 4-fluorophenyl, 4-bromophenyl, 4-cyanophenyl, 3,4-dichlorophenyl or cycloheptyl, or where R is tert-butyl, and X pre is 2-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, 4-cyanophenyl, 4-azidophenyl, 3,4-dichlorophenyl, 2,3,4,5,6- pentafluorophenyl, norpentyl, cyclohexyl, cycloheptyl or ethynyl or where R is isopropyl and X is 4-nitrophenyl, cyclohexyl or cycloheptyl; or where R is norm-propyl and X is 2-bicyclo (2.2.1) heptyl or cyclohexyl-3-enyl.

 In accordance with other aspects of the present invention, the pesticidal compounds and compositions mentioned above are used to kill certain pre-selected species of insects.

 The compounds of formula (I) can be used to control arthropods, for example parasitic insects and mites. Therefore, another aspect of the present invention is also a method of combating arthropod animal parasites, comprising treating the animals with an effective amount of a compound of formula (I).

 For these purposes, the compounds of formula (I) can be used both by themselves and in the form of known diluted preparations, for example, solutions, aerosols, varnishes, foams, dusts, powders, aqueous suspensions, pastes, gels, shampoos, ointments, solid fuels, solid sources of vapors, for example briquettes emitting vapors of the active substance, wettable powders, granules, sprays, emulsion concentrates, oil suspensions, oil solutions, impregnated objects or rinse preparations. Bath concentrates are not used on their own, but are diluted with water, after which the animals are placed in a bath filled with a solution. Spraying is done manually or using devices that create a strong jet or devices for volumetric spraying. Animals, plants, or surfaces can be spray-sprayed in a high volume method or surface treated in a low volume or ultra low volume method. Treatment with aqueous suspensions may be carried out in the same manner as with sprays or aqueous bath solutions. Processing dusts can be carried out using special devices for spraying, or (if used for treating animals) they can be placed in perforated bags, hung on trees or attached to bars for rubbing animals. Pastes, shampoos and lubricants can be applied manually or spread over the surface of an inert material. Watering preparations are applied in small portions on the back of the animal so that all or most of the liquid remains on the animal.

 The consumption of the compound of formula (I) during processing of an animal may vary depending on the nature of the compound, the time interval between treatments, the type of preparation used for processing and the intended parasite, however, as a rule, its concentration in the preparation is in the range of 0.001-20.0 0.01-10 wt. The amount applied to the animal compound depends on the method of application, the size of the animal, the concentration of the compound in the preparation used, the degree of dilution of the preparation, and the type of preparation. Usually it is in the range from 0.0001 to 0.5% (with the exception of undiluted preparations, such as watering preparations, in which the concentration of the compound of formula (I) is in the range from 0.1 to 20.0, preferably from 0, 1 to 10%).

 The compounds of formula (I) can be used for the treatment and protection of plants. In this case, the active component is used in effective, from the point of view of acaricidal and insecticidal activity, quantities. The consumption of the active component in this case depends on the nature of the compound used, the type of preparation, the method of its use, the nature of the plants, the alleged pests and other factors. Typically, when processing crops, its consumption is 0.001-3, preferably 0.01-1 kg / ha. Typically, the concentration of the compounds of formula (I) in preparations for processing crops is in the range between 0.0001-50, preferably 0.1-15 wt.

 Crops for the processing of which the proposed preparations can be used include cotton, wheat, corn, rice, sorghum, soy, grapes, tomatoes, potatoes, fruit trees and spruce.

 Dusts, greases, pastes, surface and volume sprays and aerosols are used for this purpose in the manner described above. The concentration of the compounds of formula (I) in them is in the range of 0.001-20 wt.

 It was found that the compounds of formula (I) are active against houseflies (Musca domestica), as well as other arthropod parasites, including tetranychus urticae Plutella xylostella, various species of Culex and Blatella germanica. Therefore, they can be used to combat arthropods, such as insects and ticks, in any area where they are harmful, in particular in agriculture, animal husbandry, medicine, and everyday life.

 Parasite insects that can be used to control the proposed compounds include Coleoptera orders (e.g., Anobium, tribolium, Sitophilus, Deabrotica, futhonomus, or various Anthrenus species), Lepidoptera (e.g., Ephestia, Plutella, Chilo, Heliothis, Spodoptera, or various fineola species), Diptera (e.g. Musca, Aedes, Culex, Glossina, Stomoxys, Haemotobia, Tabanus, Hydrotaea, Lucilia, Chrysomia, Callitroga, Dermatobia, Hypoderma, Liriomyza, and various types of Melophagus), Phthiraptera (e.g., Malophaga, and Anophura, e.g. Pediculus humanus capitis, Pediculus humanus phythiruspubis Linognathus and Haematopinus), Hemiptera (e.g. Aphis, Bemisia, Aleurodes, Nibopavata, Nephrotetis or various species of Cimex), Orthopter a (e.g. Schisticerca or various Acheta species), Dictyoptera (e.g. Blatella, Periplaneta or various Blatta species), Hymenoptera (e.g. Solenopis or various Monomorium species), Isoptera (e.g. various Reticulitermes species), Siphopartera (e.g. Clenocphalides or Pulex), Thysanura (e.g., various species of Lepisma), Dermaptera (e.g., various species of Forficula), and Pscoptera (e.g., various species of Peripsocus).

 Tick parasites include, for example, various species of the genus Boophilus, Phipiceplialus, Amblyomma, Hyalomma, Ixodes, Haemaphysalis, Dermocentor and Anocentor, as well as manges, such as Sarcoptes Scabiei and Tetranychus, Psoroptes, Psorergates, Dates, Notices.

 The compounds of the invention can be used in combination with one or more other active components (for example, pyrethroids, carbamates and organophosphates) and / or attractants, fungicides, and the like. It was found that the activity of the proposed compounds can be increased by adding synergists to them, for example, one of the synergists belonging to the class of oxidase inhibitors, in particular piperonyl butoxide or N1A 16388; another compound in accordance with the present invention or a pyrethroid having pesticidal activity. If an oxidase inhibitor is used as a synergist, the ratio between it and the compound of formula (I) in the preparation is between 25: 1-1: 25, for example, about 10: 1.

 The stabilizers introduced into the preparation to prevent possible chemical decomposition of the compounds may be, for example, antioxidants, for example tocopherol, butyl hydroanisole and butyloxytoluene, and acceptors, for example epichlorohydrin.

 The proposed types of pesticidal compositions have the required high pesticidal activity, especially when they are used together with a synergistic active ingredient, and these compositions are biodegradable. These pesticidal compositions have significant pesticidal activity against such harmful insects as common housefly, black and red cockroaches, moths, aphids, mosquito larvae, bugs, etc.

In accordance with the present invention, there is provided a compound characterized by the formula RC (CH ₂ O) ₃ CX, in which R and X are each organic substituents located in the 4th and 1st position, respectively, in said compound. It was found that this class of compounds includes a number of chemicals that have significant pesticidal activity. In the table. Tables 1 and 2 show relative efficiencies regarding the eradication of house flies and black cockroaches using a number of compounds that meet the above formula, when using these compounds both in pure form or together with synergetic piperonyl butylate (PB). The following abbreviations are used in these tables: PL-phenyl, n-normal, i-iso, S-secondary, t-tertiary and c-cyclo, Pr-propyl; Bu-butyl; Pen-pentyl; Hex-hexyl; Hept-heptyl.

The proposed pesticides are characterized by pesticidal activity, determined through a 50% lethal dose of LD, expressed in micrograms of pesticide per gram of live weight of the selected insect, and this value is not more than about 400. So, for example, such activity was detected in relation to home a fly. The proposed pesticides alternatively or additionally have pesticidal activity expressed as a 50% lethal dose of LD ₅₀ in micrograms of pesticide per gram of the weight of the selected insect, not exceeding about 60 and more, preferably not exceeding about 20. Such activity was shown when using an insecticide against home flies.

The use of synergists along with pesticides is a well-known fact; a detailed discussion of this problem is given in [2]
The proposed compounds become even more effective together with synergists who act in such a way that they inhibit microsomal P-450 cytochrome oxidases, which detoxify the pesticide, providing a longer period of action of the pesticide and therefore its higher toxicity.

 The proposed compositions can be used in combination with an inert carrier, which serves as a diluent or carrier for active pesticides. For example, a toxic substance can be dissolved in hydrocarbons obtained from oil, tetrahydrofuran, acetone, ethylene glycol monoalkyl ether (cellosolve), as well as other suitable inert carriers before use. Alternatively, the toxic substance may be adsorbed on a solid inert carrier such as talc, clay, finely divided silica and the like.

 Toxicity to house flies depends on the nature of both the R-substituent and the X-substituent, which is presented in table. 1, the data of which are the main evidence of the effectiveness of the proposed compounds. Compounds 1,4-bis-substituted-2,6,7-trioxabicyclo (2.2.2) octanes were tested both in pure form and together with piperonyl butylate (PB).

 The toxicity of the proposed compounds in relation to black cockroaches on the example of the topical use of 1,4-bis-substituted-2,6,7-trioxabicyclo (2.2.2) octanes was tested, while the substance was used both in pure form and together with piperonyl butylate. The obtained test results are presented in table. 2.

 Determination of biological activity.

 A number of proposed compounds were obtained and tested. Tests were conducted on insecticidal activity in relation to Musca domestica, both with and without synergist.

From the results of these tests it follows that each of the following compounds has a higher insecticidal activity (lower LD ₅₀ ) than 1- (n-butyl) -4- (tert.butyl) -2,6,7-trioxabicyclo- [ 2.2.2] octane (compound 51 in table 1 with LD ₅₀ 450 μg / g) without a synergist and higher activity with a synergist than 1-phenyl-4- (tert.butyl) -2,6,7-trioxabicyclo [ 2.2.2] octane (compound 17 in table. 1 with LD ₅₀ 23 μg / g, with synergist). In the tested compounds, the 4th substituent was tert-butyl, and the 1st substituent was 3-chloro-4-methoxyphenyl, 4-iodophenyl, 3-cyanophenyl, 4-cyano-2-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl (tolyl ), 2-bicyclo [2.2.1] heptyl, cyclooctyl, 3-cyano-4-methylphenyl, 3-methoxy-4-chlorophenyl, 3-ethylphenyl, 4-trimethylsilylethinyl phenyl, 4-methoxy-3-cyanophenyl and 4-vinylphenyl. In addition, the following compounds were tested and showed the same high activity: 1- (3,4-dibromocyclohexyl) -4- (n-propyl) -2,6,7-trioxabicyclo [2.2.2] octane, 1- (4- cyanophenyl) -4-allyl-2,6,7-trioxabicyclo [2.2.2] octane, 1- (4-ethylphenyl) -4-phenyl-2,6,7-trioxabicyclo [2.2.2] octane, 1- ( 4-chlorophenyl) -4-cycloheptyl-2,6,7-trioxabicyclo [2.2.2] octane, 1- (4-cyanophenyl) -4-isobutyl-2,6,7-trioxabicyclo [2.2.2] octane, 1 - (4-cyanophenyl) -4- (sec. Butyl) -2,6,7-trioxabicyclo [2.2.2] octane, 1- (4-cyanophenyl) -4- (1-methylprop-2-enyl) -2 , 6,7-trioxabicyclo [2.2.2] octane and 1- (4-trimethylsilylethinyl phenyl) -4- (phenyl) -2,6, 7-trioxabicyclo [2.2. 2] octane.

PRI me R 1. 50% lethal dose of LD ₅₀ for house flies.

 The compounds indicated in the table. 1, were tested to determine their insecticidal activity, and these compounds were dissolved in acetone or tetrahydrofuran if they were insoluble in acetone. A number of successive solutions were obtained using the same solvent. Compound solutions of 0.5 microliter volume were applied topically to the ventrum of the abdominal cavity of anesthetized adult female domestic flies (Musca domestica); SCR species 3-5 days after birth, each fly weighing 20 mg.

Toxicity studies were conducted by treating (topical) house flies using piperonyl butylate in an amount of 250 micrograms per gram, 2 or 3 hours before the use of the toxic substance. The treated flies were given sugar and water, and mortality was determined after 24 hours at 25 ° ^C. Data presented in Table. 1 are indicated as lethal doses, expressed in micrograms of a toxic substance per 1 g of insect weight, required to kill 50% of flying insects, these data are designated as 50% lethal doses of LD ₅₀ .

 In the table. Figure 1 shows the relationships between structure and activity for compounds tested on flies as well as on flies pretreated with piperonyl butylate. Many of these compounds are active in the same range for this type of test as pesticides currently manufactured by the industry.

Significant insecticidal activity against common house flies was detected with appropriate combinations of the R-substituent and X-substituent. These combinations are as follows:
R is normal propyl, isopropyl, normal butyl, secondary butyl, tert-butyl, cyclopentyl, cyclohexyl or phenyl, and X is normal. butyl, normal. pentyl, cyclohexyl, cycloheptyl, 4-cyanophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-nitrophenyl, 4-azidophenyl, pentafluorophenyl, 2-bicyclo [2.2.1] heptyl, phenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, ethynyl or cyclohex-3-enyl.

 Other X or R substituents that can provide activity are substituted cycloalkanes or cycloalkenes containing from 5 to 10 carbon atoms. R may also provide activity when it is a substituted phenyl group. It is preferred that R is not phenyl when X is phenyl or 4-fluorophenyl.

Compounds characterized by pesticidal activity include those in which R is straight or branched propyl or butyl, or phenyl or cycloalkyl containing from 3 to 10 carbon atoms, and X is cycloalkyl or cycloalkenyl containing from 6 to 10 carbon atoms, or substituted phenyl. Another group of compounds having pesticidal activity are compounds in which R is straight or branched propyl or butyl, or phenyl or cycloalkyl containing 5 or 6 carbon atoms, and X is cyclohexyl, cycloheptyl, cyclohexenyl, ethynyl or phenyl substituted halo, cyano, azido, nitro or C _1-2 alkyl, wherein said C _1-2 alkyl is substituted with 1-3 halogen atoms. Another group of active compounds is a group of compounds in which R is normal propyl, straight or branched butyl, cyclopentyl or cyclohexyl, and X is cyclohexyl, cycloheptyl or phenyl substituted at the 3-position or 4-position with one or several halo, cyano, azido, or nitro. Another group of active compounds are those compounds in which R is phenyl and X is phenyl substituted at the 3-position and / or 4-position with chlorine and / or bromine.

Compounds that have been prepared and tested to determine their insecticidal activity, and which are characterized by very high activity (in general, their 50% lethal dose of LD ₅₀ is less _than or equal to about 5.5 micrograms / g live weight, in those cases when used together with piperonyl butylate) are such compounds in which:
X is 4-chlorophenyl and R is normpropyl, n-butyl, secondary butyl, tert-butyl, cyclopentyl, cyclohexyl or phenyl;
R is tert-butyl, and X is cyclohexyl, cyclopentyl, 4-fluorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-cyanophenyl or 3,4-dichlorophenyl; and
R is cyclohexyl, and X is cyclohexyl, cycloheptyl, 4-fluorophenyl, 4-bromophenyl, 4-cyanophenyl or 3,4-dichlorophenyl.

 Summarizing the above, we can say that R and X can be almost any organic substituents that provide the desired insecticidal activity. Thus, insecticidal activity has been established in those cases where X and R are normal alkyl, branched alkyl, cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl substituents. While not all compounds with these substituents are active, nevertheless there are many suitable combinations. Further, simple tests conducted on house flies, or similar tests conducted with any other insects, allow you to quickly identify those combinations that are suitable for use in order to destroy any particular insect.

 PRI me R 2. Tests with other insects.

The compounds indicated in the table. 2, were tested to determine their toxicity to adult male black cockroaches (Periplaneta Americana). The test consisted of applying the solutions to be tested, as described in Example 1, to the thorax region using one microliter of carrier solution per insect. In each case, the cockroaches were also tested after preliminary topical treatment with piperonyl butylate in the amount of 250 micrograms / g live weight 2 hours before the administration of trioxabicycloactan. -WIDE 50% lethal dose LD ₅₀ were determined after 24 hours at 25 ^C. Compounds to be tested were very susceptible to the synergist piperonyl butoxide with achievement resulting efficiency similar to that which was achieved with tests on houseflies domestic treated butoxide piperonyl, with the exception of two compounds (13 and 38), which are about 10 times more toxic for domestic flies than for cockroaches. Other tests have shown that compound 6 is also toxic to mosquito larvae, aphids that live on black beans, red cockroaches, and bed bugs. Thus, the wide range of efficacy of the new class of pesticides mentioned above has been confirmed.

 PRI me R 3. Experiments with other synergists.

-(2-метилпропил)

-(2-пропинил) фенилфосфатом при концентрации, равной 125 микрограмм/г живого веса или синергетиком: 0,0-диэтил 0-фенил фосфоротиоатом при концентрации 50 микрограмм/г живого веса. В этих испытаниях синергист и инсектицид были использованы одновременно с тем, чтобы наиболее близко смоделировать ситуации, связанные с применением. Эти синергисты имеют относительно низкую стоимость и токсичность для млекопитающих. Многие соединения таким образом являются пригодными и дают экономический эффект, поскольку синергисты обеспечивают улучшение инсектицидной активности триоксабициклооктанов, применяемых для уничтожения насекомых.Other synergists, which are known to be inhibitors of oxidative detoxification, can be used instead of piperonyl butylate. This effect has been confirmed in housefly trials using a compound in which R is tertiary butyl and X is 4-chlorophenyl. The synergistic effect achieved with the use of piperonyl butylate in an amount of 250 micrograms / g was also achieved in cases where this synergistic was replaced by others:

- (2-methylpropyl)

- (2-propynyl) phenylphosphate at a concentration of 125 micrograms / g live weight or a synergist: 0,0-diethyl 0-phenyl phosphorothioate at a concentration of 50 micrograms / g live weight. In these trials, a synergist and insecticide were used simultaneously to most closely simulate application-related situations. These synergists have relatively low cost and toxicity to mammals. Many compounds are thus suitable and give an economic effect, since synergists provide an improvement in the insecticidal activity of trioxabicyclooctanes used to kill insects.

 PRI me R 3B. In experiments conducted on house flies using the same compound as in Example 3, but with piperonyl butoxide containing 1 g / g of active substance, the same activity was observed as with less piperonyl butoxide.

 Even with a content of piperonyl butoxide of 25 g / g of active substance, the resulting preparation has the same activity.

 PRI me R 4. Experiments to determine the toxicity to mammals.

The mammalian toxicity level of the two compounds of the present invention was determined as follows. These two compounds were individually dissolved in olive oil, the solution thus obtained was administered intraperitoneally to mice to determine mortality after 24 hours. These compounds were as follows: R was tert-butyl and X was cyclohexyl (compound 60); R was isopropyl, and X was cyclohexyl (compound 59). The 50% lethal injection LD ₅₀ values for the tert-butyl compound and the isopropyl compound are respectively more than 200 and more than 500 milligrams / kg of live weight.

Thus, the proposed compounds are characterized by low toxicity to mammals, while the 50% lethal dose of LD ₅₀ is more than 200 milligrams / kg of live weight. Toxicity to mammals can vary greatly depending on the type of vehicle, the route of administration, and the type of mammal.

 The proposed compounds have significant activity when used as pesticides, against a large class of different types of insects. These compounds are readily biodegradable.

 One of the advantages of the proposed insecticides is that their pesticidal activity is significantly higher than their toxicity to mammals. Therefore, those small amounts of these pesticides that are used to control parasites will not have a harmful effect on mammals. It is clear that this has a positive effect on the environment. In addition, the claimed pesticides decompose biologically. The applicant proposed a new wide class of pesticides, which in their chemical structure differ significantly from known pesticides. Therefore, they differ from non-analogous known pesticides and surpass them.

 PRI me R 5. Competitive or preliminary use of a synergist.

 A synergist is equally or more effective when used with an insecticide, in this example with compound 6, when it is used two hours earlier.

Синергист

а

и-

ное
РВ 5 мкг/муха 1,25 1,0
NIA 16824 2,5 мкг/муху 1,0 0,35
R33865 1 мкг/муху 0,6 0,6
Эти данные демонстрируют практически равную эффективность совместного применения и предварительной обработки синергистом. 111А 16824 (

-(2-метилпропил)

-(2-пропинил) фенилфосфонат описан в описании в примере 3; R 33865

-

-диэтил

-фенил фосфорнат описан также. Все эти соединения, как и бутилат пиперонила, (РВ), являются известными синергистами инсектицидов.A. Compound N 6

Synergist

and

and-

new
RV 5 mcg / fly 1.25 1.0
NIA 16824 2.5 mcg / fly 1.0 0.35
R33865 1 mcg / fly 0.6 0.6
These data demonstrate almost equal efficiency of joint application and preliminary processing by the synergist. 111A 16824 (

- (2-methylpropyl)

- (2-propynyl) phenylphosphonate is described in the description in example 3; R 33865

-

diethyl

α-phenyl phosphornate is also described. All of these compounds, like piperonyl butylate (PB), are known synergists of insecticides.

 PRI me R 6. The ratio between synergist and insecticide.

 The ratio of synergist to insecticide lies in the range from 1 part of synergist to 20 parts of insecticide, up to 200 parts of synergist to 1 part of insecticide. See Example B for Compound 6 and Example C for Compound 6, and Example C for Compound 24.

B. Compound 6 + PB / μg / g kill
5 mcg / g + 0 10
5 μg / g + 0.5 μg / g 20
Synergist insecticide ratio 110 1.25 mcg / g 0 0
1.25 mcg / g 250 mcg / g 50
Synergist Insecticide Attitude 2001
C. Compound 24 + synergist RV destruction
250 mcg / g 0 30
250 mcg / g 12.5 mcg / g 40
Synergist insecticide ratio 1 20
1.9 mcg / g 0 0
1.9 mcg / g 250 mcg / g 50
Synergist ratio insecticide 1321
PRI me R 7. The use of insecticidal compounds in the destruction of plant insects.

 A leaf of a plant with a diameter of about 3 inches was sprayed with 3 ml of a 1% solution of compound N 6 in acetone. Adults and nymphs of insects parasitizing on the giant coon, Oneofelus facialus, feeding on this plant, were placed on the treated sheet. All insects died in 12 hours. In the control experiment, none of the insects placed on a sheet of the same size, sprayed with acetone only, died in 12 hours.

 The following table provides additional data showing the effectiveness of the compounds and methods of their use. The test compounds are dissolved in acetone and applied as a solution topically to mature individuals of the housefly according to the procedure described earlier in the description. When using a synergist, it is applied topically in an amount of 250 micrograms / piperonyl butoxide per gram of fly two to three hours before application of the test compound. Compounds are characterized by reduction for each of them its structure. These compounds are active at a dose below 23 μg / g with piperonyl butoxide in synergistic compositions, it is shown that their activity is below 40 μg / g when using the tested compounds in pure form.

 The active substance and the synergist can be applied together with the same impressive result, but the previously presented data do not indicate the simultaneous application of the toxic substance and the synergist. Applicants used the pre-processing technique.

 PRI me R 8. The activity of representative pesticides is higher compared with known pesticides.

In the table. 3 shows the toxicity values (locally) for houseflies at 25 ° ^C.

The data presented indicate that the compounds characterized by the formula RC (CH ₂ O) ₃ CX are effective pesticides. R or X may be alkyl, alkynyl, cycloalkyl or cycloalkenyl, each of which may be normal, branched or substituted, or they may be aryl or substituted aryl. In those cases where R is straight or branched alkyl, cycloalkyl or aryl, the resulting compounds give a useful effect. It is preferred that the number of carbon atoms in R be in the range of 3 to 10. It is more preferred that R is n-propyl, tert-butyl, cyclohexyl, cyclopentyl, iso-propyl, n-butyl, secondary butyl or phenyl. X preferably should be cycloalkyl or substituted cycloalkyl, or cycloalkenyl containing from 6 to 10 carbon atoms, normal alkyl, alkynyl or substituted phenyl. Effective pesticides are those pesticides in which X-substituents are cyclohexenyl and cycloheptenyl. Other suitable substituents include norm peptyl, cyclohex-3-enyl and 2-bicyclo [2.2.1] heptyl. Substituents on the phenyl group in those cases where the phenyl group is group X are halogens, cyano, nitro or azido groups.

, 287-293 (1979);
Зависимости между структурой и токсичностью 2,6,7-триоксабицикло(2.2.2)октанов и аналогичных соединений. Дж.Е.Касида, М.Это, А.Д.Мосциони, Дж.Л.Энгел, Д.С.Милбрат и Дж.Г.Веркаде. Токсикология и прикладная фармакология, 36, 261-279 (1976) (Structure Toxicity Relation ships of 2,6,7-Trioxabicyclo(2.2.2), octanes and Related Compoudns, I.E.Casida; M.Eto; A.D.Moscioni; I.L.Engel; D.S.Milbrath; I.G.Verkade; Toxicology and Applied pharmacology;

, 261-279 (1976);
Ядерно-магнитный резонанс в полициклических соединениях. II. Связь дальнего действия Н¹ H¹ и H¹ P³¹ в некоторых производных адамантана и бицикло(2.2.2)октана. Е.Дж.Борос, К.Дж.Коскран, Р.В.Кинг и Дж.Г.Беркаде, IACS 88, 1140-1143 (1966) (Nuclear-Magnetic Resonance in Polycyc lie Compaunds II Song-Range H¹-H¹ и H¹-P³¹ Coupling in Sona Ackamantane and Biciclo (2.2.2) octane Derivativer, E.I.Boros; K.I.Coskran, R.W.King; I.G.Werkade; IACS,

, 1140-1143 (1966);
Необычное поведение гексафторбензола и бензола в эффекте смещения ароматического ядерно-магнитного резонанса. Р.Д.Бертранд, Р.Д.Комптон и Дж.Г.Веркаде, IACS, 92, 2702-2709 (1970) (Unusual Behavior of Hexafluorobenzene and Benzene in the Aromatic Nuclean Magnetic Resonance Shift Effect. R.D.Bertrand, R.D.Compton, I.G.Verkade; IACS,

, 2702-2709 (1970);
Новый общий синтетический способ к сложным ортоэфирам карбоновой кислоты с мостиковой связью. Е.Дж.Кокей и Н.Раджу. Tetrahedron Letters,

, 5571-5574 (1983) (A. New General Synthetic Route to Bridged Carboxylic Ortho Esters E.I.Cokey; N.Raju; Tetrahedron Letters, 24, 5571-5574 (1983).Synthesis Procedures. Methods of obtaining compounds characterized by the above general formula are presented in the following publications:
Dependencies between the structure and toxicity of 1-substituted-4-alkyl-2,6,7-trioxabicyclo [2.2.2] octanes. D.S. Milbrat, D.L. Engel, J.G. Vercade and J.E. Casida. Toxicology and Applied Pharmacology, 47, 287-293 (1979); (Structere Toxicity Relation ships of 1-Substituted-4 alkyl-2,6,7-trioxabicyclo (2.2.2) octanes, DS Milbrath; ILEngel; IGVerkade; IECasida Toxicology and Applied Pharmacology;

287-293 (1979);
Dependencies between the structure and toxicity of 2,6,7-trioxabicyclo (2.2.2) octanes and similar compounds. J.E. Casida, M.Eto, A.D. Moscioni, J.L. Engel, D.S. Milbrat and J.G. Vercade. Toxicology and Applied Pharmacology, 36, 261-279 (1976) (Structure Toxicity Relation ships of 2,6,7-Trioxabicyclo (2.2.2), octanes and Related Compoudns, IECasida; M.Eto; ADMoscioni; ILEngel; DSMilbrath; IGVerkade ; Toxicology and Applied pharmacology;

261-279 (1976);
Nuclear magnetic resonance in polycyclic compounds. II. The relationship between long-range H ¹ H ¹ and H ¹ P ³¹ in some derivatives of adamantane and bicyclo (2.2.2) octane. E.J. Boros, C.J. Koskran, R.V. King and J.G. Berkade, IACS 88, 1140-1143 (1966) (Nuclear-Magnetic Resonance in Polycyc lie Compaunds II Song-Range H ¹ -H ¹ and H ¹ -P ³¹ Coupling in Sona Ackamantane and Biciclo (2.2.2) octane Derivativer, EIBoros; KICoskran, RWKing; IGWerkade; IACS,

1140-1143 (1966);
Unusual behavior of hexafluorobenzene and benzene in the effect of displacement of aromatic nuclear magnetic resonance. R.D. Bertrand, R.D. Compton and J.G. Verkade, IACS, 92, 2702-2709 (1970) (Unusual Behavior of Hexafluorobenzene and Benzene in the Aromatic Nuclean Magnetic Resonance Shift Effect. RDBertrand, RDCompton, IGVerkade; IACS

2702-2709 (1970);
A new general synthetic method for bridged carboxylic acid orthoesters. E.J. Kokey and N. Raju. Tetrahedron Letters,

5571-5574 (1983) (A. New General Synthetic Route to Bridged Carboxylic Ortho Esters EICokey; N. Raju; Tetrahedron Letters, 24, 5571-5574 (1983).

, 4571-4577 (1955).Intermediates for these reactions are described: ketene acetals. Xxxiv. Acetal tetra- and pentamethylene ketene. S.M. McAlvin and R.E. Starn, IACS 77, 4571-4577 (1955), (Ketene Acetals, XXXIV, tetra and Pentamethylene Ketene Acetals, SM Mc Elvain; REStarn, IACS,

4571-4577 (1955).

, 1697-1699 (1954);
Простые циклические эфиры, полученные путем пиролиза сложных карбонатных эфиров. Д. Б. Паттисон, IACS 79, 3455-3456 (1957) (Cyclic Ethers Made by Pyzolysis of Carbonate Ethers, D.B.Pattison; IACS;

, 3455-3456 (1957);
Два характерных метода (А и В) были использованы для получения триоксабицикло октанов (табл. 4). В каждой из процедур в качестве исходного материала использовали триол, синтезированный из соответствующего замещенного ацетальдегида путем реакции оксиметилирования и последующей перекрестной реакции Канницаро (реакция образования спиртов и кислот при окислении восстановлении ароматических альдегидов, пер.). (Реакция описана Дермeром и Соломоном, в 1954 г. и Кетшлафом и др. в 1963 г.). Реакция проводилась по следующей схеме:
RCH₂CHO

RC(CH₂OH)₃
Каждый триоксабициклооктан давал соответствующие характеристики протонного ядерного магнитного резонанса и соответствующие характеристики масс-спектра. Сокращения, используемые при описании данных спектра ядерно-магнитного резонанса соответствуют: S синглет, d дублет, 2 х d два дублета, dd дублет дублетов, t триплет, 2 х t два триплета, g квартет и m мультиплет.Obtaining trimethylolisobutane by condensation of isovalerian aldehyde and formaldehyde. M.M. Ketshlakh, D.M. Rutkovsky and R.A. Eppel. Oxosynthesis, production by the method of oxosynthesis of aldehydes of alcohols and secondary products based on them. All-Union Research Institute of Petrochemical Processes, 156-163 (1963);
The development of condensation of tolenes. O.S. Dermer and P.V. Solomon. IACS 76, 1697-1699 (1954) (Extension of Tollens Condensation; OCDermer; PWSolomon. IACS,

, 1697-1699 (1954);
Cyclic ethers obtained by pyrolysis of carbonate esters. D. B. Pattison, IACS 79, 3455-3456 (1957) (Cyclic Ethers Made by Pyzolysis of Carbonate Ethers, DBPattison; IACS;

3455-3456 (1957);
Two characteristic methods (A and B) were used to obtain trioxabicyclo octanes (Table 4). In each of the procedures, a triol synthesized from the corresponding substituted acetaldehyde by the oxymethylation reaction and the subsequent cross-reaction of Cannizzaro (the reaction of the formation of alcohols and acids during oxidation reduction of aromatic aldehydes, trans.) Was used as the starting material. (The reaction is described by Dörmer and Solomon, in 1954 and Ketschlaf and others in 1963). The reaction was carried out as follows:
RCH ₂ CHO

RC (CH ₂ OH) ₃
Each trioxabicyclooctane gave the corresponding characteristics of proton nuclear magnetic resonance and the corresponding characteristics of the mass spectrum. The abbreviations used to describe the data of the nuclear magnetic resonance spectrum correspond to: S singlet, d doublet, 2 x d two doublets, dd doublet of doublets, t triplet, 2 x t two triplets, g quartet and m multiplet.

R

X где R^I может быть алкилом или арилом, предпочтительно метилом или этилом. Например, смесь 2-т-бутил-2-гидроксиметил-1,3-пропандиола (R t-Bu) (0,4 г, 2,5 ммоль), триметил ортоциклогексанкарбоксилата (Хос-Нeх; R^I СН₃) (0,5 г, 2,5 ммоль) и 4-толуолсульфокислоты (10 мг) нагревают до 160^оС до тех пор, пока не отгонится метанол. Остаток сушат в вакууме (при 1 мм Hg) и затем пропускают через короткую колонку, наполненную оксидом алюминия, получая триоксабициклооктан 60 (Хос-Нeх; Rt-Bu) (0,6 г, 95%). Аналогичные методики используют для получения соединений 2-9, 13, 14, 17-19, 21, 23-27, 38, 39, 51, 59, 60 и 65.Method A. Acid catalyzed triol condensation with orthocarboxylate. (Boros et. Al. 1966; Bertrand et. Al. 1970). The reaction equation has the following form:
R

R

X wherein R ^I may be alkyl or aryl, preferably methyl or ethyl. For example, a mixture of 2-t-butyl-2-hydroxymethyl-1,3-propanediol (R t-Bu) (0.4 g, 2.5 mmol), trimethyl orthocyclohexanecarboxylate (Хос-Нех; R ^I СН ₃ ) (0 , 5 g, 2.5 mmol) and 4-toluenesulphonic acid (10 mg) was heated to ^{160 °} C until until methanol distilled off. The residue was dried in vacuo (at 1 mm Hg) and then passed through a short column filled with alumina to give trioxabicyclooctane 60 (Xos-Hex; Rt-Bu) (0.6 g, 95%). Similar methods are used to obtain compounds 2-9, 13, 14, 17-19, 21, 23-27, 38, 39, 51, 59, 60 and 65.

H₃)₃ где Y представляет собой водород или одну или более других групп, таких как галоид или трифторметил.Intermediate trimethyl orthocarboxylates are commercially available or synthesized by any of two methods illustrated by methyl esters. According to the first method, the corresponding benzotrichloride or benzotribromide (from the bromination of the corresponding toluene with N-bromosuccinimide (NBS)) is subjected to halogen substitution with methoxide (McElvain and Venerable, 1950). These methods are as follows:

H ₃ ) ₃ where Y represents hydrogen or one or more other groups, such as halogen or trifluoromethyl.

XC

XC(OCH₃)₃
Способ В. Перегруппировка ацилированного гидроксиметоксетана (Corey and Raju, 1983). Ацилирование 3-замещенных-3-гидроксиметоксетанов (полученных из соответствующего триола путем пиролиза карбонатного сложного эфира) (Pattison, 1957) дает соответствующие оксетановые сложные эфиры, которые могут перегруппировываться в присутствии эфирата трехфтористого бора с образованием триоксабициклооктанов. Уравнение реакции имеет вид:
R

_R

Например, 4-нитробензоил хлорид (2,28 г, 12,3 ммоль) в сухом дихлорметане (4 мл) добавляют к 3-изопропил-3-гидроксиметилоксетану (1,6 г, 12,3 ммоль) в сухом дихлорметане (15 мл) и сухом пиридине (2 мл) при 0^оС в атмосфере азота. Раствор перемешивают в течение ночи, затем экстрагируют водой, сушат (сульфат натрия), фильтруют и выпаривают, получая 4-нитробензоиловый эфир (3,4 г, 99%) в виде остатка, который в дальнейшем не очищают. ¹Н ЯМР (СDCl₃), δ 1,0 (6Н, д, (СН₃)₂С), 2,3 (1Н, m, С-СН), 4,55 (2Н, с, СН₂ОСО), 4,6 (4Н, dd, СН₂ОСН₂), 8,3 (4Н, q, ароматический).According to a second method, the corresponding nitrile is treated with methanol and hydrochloric acid to give the imino ester hydrochloride, and ultimately trimethyl orthocarboxylate (McElvain and Starn, 1955). This method is as follows:
Xcn

Xc

XC (OCH ₃ ) ₃
Method B. Rearrangement of acylated hydroxymethoxetane (Corey and Raju, 1983). Acylation of 3-substituted-3-hydroxymethoxetanes (obtained from the corresponding triol by pyrolysis of a carbonate ester) (Pattison, 1957) gives the corresponding oxetane esters that can rearrange in the presence of boron trifluoride etherate to form trioxabicyclooctanes. The reaction equation has the form:
R

_R

For example, 4-nitrobenzoyl chloride (2.28 g, 12.3 mmol) in dry dichloromethane (4 ml) is added to 3-isopropyl-3-hydroxymethyloxetane (1.6 g, 12.3 mmol) in dry dichloromethane (15 ml ) and dry pyridine (2 ml) at ⁰ ° C under a nitrogen atmosphere. The solution was stirred overnight, then extracted with water, dried (sodium sulfate), filtered and evaporated to give 4-nitrobenzoyl ether (3.4 g, 99%) as a residue, which was not further purified. ¹ H NMR (CDCl ₃ ), δ 1.0 (6H, d, (CH ₃ ) ₂ C), 2.3 (1H, m, C-CH), 4.55 (2H, s, CH ₂ OCO) 4.6 (4H, dd, CH ₂ OCH ₂ ); 8.3 (4H, q, aromatic).

This residue was dissolved in dry dichloromethane (15 ml) under nitrogen, cooled to (-) 55 ^{° C} and 2 ml of boron trifluoride etherate. The mixture was allowed to warm to room temperature and was quenched with triethylamine, evaporated to dryness and partitioned between water and dichloromethane. The organic layer was separated, dried (potassium carbonate) and evaporated.

The residue is purified by passing through a short column with basic alumina,
to obtain trioxabicyclooctane 28
(X 4 NO ₃ Ph; R1 Pr) (1.7 g, 50%)
Compounds 28-32, 43, 53, 61, 62, 71, 72, and 74 are similarly prepared.

Claims (5)

1. DERIVATIVES OF 1,4-BIS-SUBSTITUTED 2,6,7-TRIOXABICYCLO [2 2 2] OCTANES of the general formula
RC (CH ₂ O) ₃ CX,
where R propyl, butyl, C ₃ C _{1 0} -cycloalkyl or phenyl;
XC ₆ C _{1 0} cycloalkyl, C ₆ - C _{1 0} cycloalkenyl, C ₂ C ₆ alkynyl or phenyl substituted with one or more substituents selected from halogen, cyano, azido or nitro groups or C ₁ C ₂ alkyl optionally substituted with 1-3 halogen atoms, with the proviso that when X 4 is fluorophenyl, R must not be phenyl. 2. The compound according to claim 1, characterized in that R is cyclohexyl, cycloheptyl, cyclohexenyl, ethynyl or phenyl substituted with a halogen atom, cyano, azido or nitro group or C ₁ C ₂ alkyl, and C ₁ C ₂ alkyl is substituted 1-3 halogen atoms, provided that when X 4 is fluorophenyl, R is other than phenyl.  3. The compound according to claim 1 or 2, characterized in that R is n-propyl, butyl, cyclopentyl or cyclohexyl, and X is cyclohexyl, cycloheptyl or phenyl substituted at the 3rd and / or 4-position with substituents independently selected from the group including halogen, cyano, azido or nitro.  4. The compound according to claim 2 or 3, characterized in that R is phenyl and X is phenyl substituted in the 3rd and / or 4th positions with a substituent independently selected from the group consisting of chloro and bromo.  5. The compound according to claim 1, characterized in that it has pesticidal activity. Priority by signs:
01/30/84 at RC ₆ C _{1 0} -cycloalkyl, propyl or butyl, X has the meanings indicated in claim 1;
01/23/85 at RC ₆ C _{1 0} -cycloalkyl, propyl, butyl or phenyl, X has the meanings indicated in claim 1.

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