The method of obtaining derivatives of substituted 2-nitroguanidine and methods of making intermediates

 

Describes how to obtain the substituted derivatives of 2-nitroguanidine formula R2-N(H)-C(=N-NO2)-N(H)-CH(R1)-Het, and not necessarily its E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in free form or in the form of salts, where R1, R2, Het, have the meanings indicated in the claims, characterized in that the compound of the formula Q-A-Q (IIa), where A, Q take the values specified in the claims, and not necessarily its E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in free form or in the form of salts is subjected to hydrolysis in the environment, the pH value of which is less than 6. Also the methods of obtaining the intermediate compounds. 3 s and 5 C.p. f-crystals, 27 PL.

The invention relates to a method of a new type of receipt substituted derivatives of 2-nitroguanidine.

It is known that to obtain a 1,3-disubstituted 2-nitroguanidine in one-deputizing 2-nitroguanidine may be another Deputy (for example, by alkylation) (see, for example, applications EP 0375907, 0376279 and 0383091). Because of the presence of three reactive hydrogen atoms used in these reactions as a source of material one-deputizing 2-nitroguanidine all Prem selectivity and lead to the formation of undesirable products of substitution. In the above-mentioned European patent applications describes how to obtain the 1,3-disubstituted 2-nitroguanidine interaction one-deputizing of microestimation with primary amines in the removal of mercaptan. However, upon receipt of those proposed for use in the known methods as starting materials nitrosotoluene compounds containing leaving allylthiourea, we have to reckon with a number of difficulties regarding their availability. Later in the application EP 0483062 describes a method of obtaining compounds of formula (I), carried out by hydrolysis hexahydrotriazine.

However, it should be noted that the above-described methods for obtaining compounds of formula (I) does not meet the requirements to the chemical method in industrial production: we mean, in particular, hassle-free obtain, toxicity, stability during storage and purity of raw materials and auxiliary substances, duration of reaction, energy consumption and ensure the process volume output, the quantity and regeneration of the generated by-products and waste, as well as the purity and yield of the final product. With this in mind, still remains an urgent need to develop universitetinin way can with a high degree of reliability and efficiency to meet the specified requirements.

Based on the foregoing, the present invention was used to develop an improved method of obtaining a 1-one-deputizing and 1,3-disubstituted 2-nitroguanidine of received light by the parent compounds, which would allow to carry out targeted 1,3-dwuzamesheng without the formation of large quantities of undesirable by-products.

The object of the invention is (a) a method of obtaining the compounds of formulaand not necessarily its E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in free form or in the form of salts, where R1denotes hydrogen or C1-C4alkyl, R2denotes hydrogen, C1-C6alkyl, C3-C6cycloalkyl or residue-CH2In; Het is an unsubstituted or, depending on the possibilities for substitution in the ring system of one - to five-fold substituted by substituents selected from the group comprising halogen, C1-C3alkyl, C1-C3alkoxy, halogen-C1-C3alkyl, C1-C3halogenoalkane, cyclopropyl, halogenlampen,2-C3alkenyl,2-C3quinil,2-C3halogenoalkanes, propargyloxy, allylthio, propargite, halogenations, halogenierte, cyan and nitro, aromatic or non-aromatic, monocyclic or bicyclic heterocyclic residue, and denotes phenyl, 3-pyridyl or thiazolyl, optionally substituted with one to three substituents selected from the group comprising From1-C3alkyl, C1-C3halogenated, cyclopropyl, halogenlampen,2-C3ekenel,2-C3quinil,1-C3alkoxy, C2-C3halogenoalkanes,2-C3halogenoalkanes,1-C3halogenoalkane,1-C3alkylthio,1-C3allogenicity, allyloxy, propargyloxy, allylthio, propargite, halogenations, halogenierte, halogen, CYANOGEN and nitro.

The method differs in that gidrolizuet compound of the formula Q-A-Q (IIA)
where a denotes a direct bond or an organic residue, or a compound of the formula

where U denotes an organic residue, and in the compounds of formulas (IIA) and (IIb) Q is a

a R1, R2and Het have the meanings indicated above for formula (I), and not necessarily their E/Z-isomers, mixtures of E/Z-isomers and/or automdi E/Z-isomers, for example, in the following two isomeric forms


In accordance with this under the compounds of formula (I) above and in the following refers to the corresponding E/Z-isomers, even if they are not mentioned specifically in each case.

The compounds of formula (I) can be partially represented in the form of tautomers. In accordance with this under the compounds of formula (I) above and in the following refers to the corresponding tautomers, even if they are not mentioned specifically in each case.

The compounds of formula (I) and not necessarily their E/Z isomers and tautomers can be represented in the form of salts. The compounds of formula (I) having at least one basic centre can form, for example, an acid additive salt. Such salts are formed, for example, with strong inorganic acids such as mineral acids, for example sulfuric acid, with either phosphoric acid or halogenation acid, with strong organic carboxylic acids, such as optionally substituted, for example halogen, C1-C4alcancarao acid, for example acetic acid, such as optionally unsaturated dicarboxylic kiye acid, for example ascorbic, lactic, malic, tartaric or citric acid, or such as benzoic acid, or with organic sulfonic acids, such as optionally substituted, for example halogen, C1-C4alkane - or arylsulfonate, such as methane, cryptomelane or p-toluensulfonate. Salts of compounds of formula (I) with acids called type get is preferably in the processing of reaction mixtures.

Further, the compounds of formula (I) with at least one acidic group can form salts with bases. As such salts with bases include, in particular, metal salts, such as salts of alkaline or alkaline-earth metals, for example salts of sodium, potassium or magnesium salts, or salts formed with ammonia or with organic amines, such as morpholine, piperidine, pyrrolidine, with mono-, di -, or three(ness.)alkylamine, for example ethyl-, diethyl-, triethyl - or dimethylpropylene, or with mono-, di - or trihydroxy(ness.)alkylamino, for example mono-, di - or triethanolamine. In addition, under certain conditions, can be formed corresponding internal salts. The preferred salt according to the invention, to provide the corresponding agrochemical, and salts, in turn, mean, respectively, also available compounds of formula (I). That is true for E/Z-isomers and tautomers of compounds of formula (I) and their salts. Preferred all of them in free form.

Mentioned above in relation to the free compounds of formula (I), respectively, E/Z-isomers and tautomers, and their salts is true for compounds of formulas (IIA) and (IIb), as well as for the following compounds of formulas (IIIA) and (IIIb).

In order to more fully decode the above formula (I), (IIA), (IIb) and define the following compounds of formulas (IIIa) and (IIIb) some General concepts require the following explanations.

Under consideration as substituents halogen atoms are meant as fluorine and chlorine, and bromine and iodine, preferably represent fluorine, chlorine and bromine, particularly chlorine. Halogen represents an independent Deputy, or the part of the Deputy, as is the case in particular in halogenoalkane, allogeneically, halogenoalkane, halogennitroalkane, halogenoalkanes, halogenoalkane, halogenations or halogenierte. Considered as substituents alkyl, alkylthio-, alkeline, alkyline and alkoxide methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. As appropriate CNS residues are among the other methoxy, ethoxy, propoxy, isopropoxy or butoxy and their isomers. Alkylthio represents, for example, methylthio, ethylthio, isopropylthio, propylthio or the isomeric butylthio. If considered as substituents alkyl, CNS, alkeline, alkyline or cycloalkyl group substituted with halogen, they may be galogenirovannyie only partially, or completely. For halogen, alkyl and alkoxy fair values above. Examples of alkyl elements of these groups are from one - to three-fold substituted by fluorine, chlorine and/or bromine, methyl, such as, for example, CHF2or CF3; from one - to five-fold substituted by fluorine, chlorine and/or bromine, ethyl, as, for example, CH2CF3, CF2CF3, CF2CCl3, CF2CHCl2, CF2CHF2, CF2CFCl2, CF2CHBr2, CF2CHClF, CF2CHBrF or CClFCHClF; from one - to seven-substituted by fluorine, chlorine and/or bromine propyl or isopropyl, as, for example, CH2CHBrCH2Br, CF2FF3CH2CF2CF3or CH(CF3)2; F(CF3)CHFCF3or CH2(CF2)2CF3; 2-chlorocyclopropane or 2,2-diversicolor; 2,2-defermined, 2,2-dichlorovinyl, 2-chlorallyl, 2,3-dichlorovinyl or 2,3-dibromovinyl.

In cases where the above alkyl, CNS or cycloalkyl group substituted by other substituents, they can be single - or multi-substituted by identical or different substituents from among the above. Preferably the substituted groups have one or two other Deputy. Under consideration as Vice cycloalkenyl remnants of meaning, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Alkeneamine and alkyline groups contain unsaturated carbon-carbon bond. Typical representatives are the allyl, methallyl or propargyl, as well as vinyl and ethinyl. Double or triple bond in groups of allyloxy, propargyloxy, allylthio or propargite separated from the point of attachment to the heteroatom (O or S) is preferably a saturated carbon atom.

Similarly to the above-mentioned alkyl, alkenyl and alkynylaryl groups is presented below alkylene, alkenylamine and alkenylamine group can also be remotemachine or RA2-CH2-CH2-, -CH2- (CH3)N - and- (CH3)N-C(CH3)N. Below alkylene, alkenylamine, alkenylamine, cycloalkene, allenbyi and geterotsiklicheskie group under certain conditions substituted in the same manner as the above-mentioned alkyl, alkeline and alkyline group.

Aryl, respectively Allen denote phenyl or naphthyl, respectively phenylene or naftilan, especially phenyl, respectively phenylene.

Identified as Het heteroaryl residue represents according to the present invention is preferably a 5-7 membered aromatic or non-aromatic ring with one to three heteroatoms selected from the group comprising N, O and S. Preferred aromatic 5-6 membered ring containing as the heteroatom one nitrogen atom and optionally another heteroatom, preferably nitrogen, oxygen or sulfur, primarily nitrogen.

As was already emphasized at the beginning of the description, unexpectedly, it was found that proposed in the invention method meets the above requirements.

The method of hydrolysis according to the invention can be both acidic and basic environment. In the acidic range preferred snakeeye only from 8 to 12 and most preferably from 8 to 10. The reaction is carried out at normal pressure and at temperatures in the range from 0 to 120oC, preferably from 20 to 80oC. the Reaction is carried out in an inert towards the components of the solvent or diluent. Preferably used as solvents alcohols, such as methanol, ethanol, propanol and isopropanol, but especially water. Other suitable for these purposes solvents are, for example, ethers such as tetrahydrofuran and dioxane, as well as other solvents that do not have a negative impact on the reaction. Solvents can also be used in the form of their mixtures. It is preferable to hydrolyze the compound of formula (II) in aqueous medium or in a mixture of water and alcohol.

As acids for implementing the method according to the invention preferably acceptable mineral acids such as sulfuric acid, phosphoric acid or a halogen acid, organic carboxylic acids, such as optionally substituted, for example halogen, C1-C4alcancarao acid, for example acetic acid, such as optionally unsaturated dicarboxylic acids, for example oxalic, malonic, maleic, fumaric or phthalic sour the PTA, or such as benzoic acid, or organic sulfonic acids, such as optionally substituted, for example halogen, C1-C4alkane or arylsulfonate, for example methane - or p-toluensulfonate.

As a basis for implementing the method according to the invention is suitable preferably hydroxides of alkali and alkaline-earth metals, such as NaOH and KOH; carbonates, such as PA2CO3, NaHC3To2CO3; phosphates, such as PA3RHO4, Na2HPO4; alcoholate, such as methanolic sodium, ethanolic sodium tert-butanolate potassium; organic amines, such as morpholine, piperidine, pyrrolidine, mono-, di -, or three(ness.)alkylamine, for example ethyl-, diethyl-, triethyl - or dimethylpropylene, or mono-, di - or trihydroxy(NISS. )alkylamine, for example mono-, di - or triethanolamine, or dialkylanilines, such as N,N-dimethyl - or N,N-diethylaniline; and organic acid salts, such as sodium acetate, potassium acetate or sodium benzoate, or a mixture thereof, such as acetate or phosphate buffer.

Regarding especially preferred conditions for carrying out reactions you can refer to examples where these conditions are described in detail.

JV the strategic balance Het is unsaturated and is associated as a member of the ring through the carbon atom with the main part. Especially preferred residues Het is pyridyl, thiazolyl, tetrahydrofuranyl, dihydrofurane, furanyl, N-oxidability, oxazolyl, isoxazolyl, thienyl, morpholinyl, piperidinyl, pyridinyl and pyrazinyl; first of all, pyridyl, thiazolyl, tetrahydrofuranyl and N-oxidability; most preferably 3-pyridyl, 2-halogenase-5-yl, 2,3-dehalogenase-5-yl, 2-halogentated-5-yl, tetrahydrofuran-3-yl, 2-methyltetrahydrofuran-4-yl, 1-occupied-3-yl, 1-oxo-2-halogenase-5-yl and 1-oxo-2,3-dehalogenase-5-yl.

Also preferably, the heterocycle Het carry one to three substituent from the group comprising halogen, C1-C3alkyl, C1-C3halogenated and C1-C3halogenoalkane respectively with 1-7 halogen atoms and C1-C3alkoxy, particularly preferably chlorine or methyl.

In another embodiment, receive preferred according to the invention the compounds of formula (I), where the remainder represents a phenyl, pyridyl or thiazolyl, which may be unsubstituted or may be substituted by one or two residues from the group comprising halogen, C1-C3alkyl, C1-C3halogenated and1-C3halogenoalkane respectively with 1-7 halogen atoms I such compounds, in which
R1denotes hydrogen;
R2denotes hydrogen, C1-C3alkyl or cyclopropyl, primarily hydrogen, methyl, ethyl or cyclopropyl, primarily methyl; and
Het represents a pyridyl, 1-oxopyridine, tetrahydrofuranyl, thiazolyl or substituted respectively with one to three substituents from the group comprising halogen, C1-C3alkyl, C1-C3halogenated and1-C3halogenoalkane with 1-7 halogen atoms and C1-C3alkoxy, pyridyl, 1-oxidability, tetrahydrofuranyl or thiazolyl, primarily 2-chloropyrid-5-yl, tetrahydrofuran-3-yl, 2-methyltetrahydrofuran-4-yl or 2-chlorothiazole-5-yl.

For implementing the method according to the invention is used, on the one hand, preferably such compounds of formula (IIA), where a denotes remotemachine or branched2-C20alkylen,2-C20albaniles,2-C20akinyan,
With3-C12cycloalkyl, Allen or heterocyclyl, and group C2-C20alkylen,2-C20albaniles,2-C20akinyan,3-C12cycloalkyl, Allen and heterocyclyl optional one - or many times independently, it is not necessarily independent from each other single or repeatedly torn About, N-H or N-C1-C12the alkyl, C3-C9cycloalkenes, aryleno or heterocyclisation, or means a group-D1-D2-D3- where D1and D3independently of one another denote an optionally substituted C3-C12cycloalkyl or Allen, and D2stands With2-C20alkylen,2-C20albaniles,2-C20akinyan, O, N-H or N-C1-C12alkyl.

The most preferred bridge links And are2-C12alkylen, broken one or two phenylanaline, cyclohexylaniline or piperazinylcarbonyl residues With2-C12alkylen, cyclohexyl or phenylene or a group-D1-D2-D3- where D1and D3denote phenylene or DICYCLOHEXYL, and D2stands About or2-C4alkylen; first And indicates With2-C4alkylen.

On the other hand, for implementing the method according to the invention as starting material used is preferably the compounds of formula (IIb), where U denotes aryl, heterocyclyl,3-C12cycloalkyl or group

where A1, A2and A3independently from each other have t the formulas (IIA) and (IIb) is preferably an aromatic or non-aromatic, three-desatino ring. When rings a and U are aromatic are preferably the same ring as above for Het. In the case where a and U are non-aromatic heterocyclic rings are preferred primarily piperidinyl, piperazinil, morpholinyl, pyrrolidinyl, tetrahydrofuranyl and DIOXOLANYL.

Most preferably the remains of A1, A2and a3independently of one another denote With2-C4alkylen, primarily ethylene.

Another object of the invention is
b) the method of producing compounds of formulas (IIA) and (IIb), which differs in that the compound of the formula
T-a-T (IIIa)
or a compound of the formula

where a and U have the same values as above for formula (IIA) and (IIb), T is a

a R2has the same meaning as indicated above for formula (I), and not necessarily their E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in free form or in the form of salts, in the case of obtaining the compounds of formula (IIIa) is subjected to interaction with two equivalents, and in the case of obtaining the compound (IIIb) with three equivalents connection formam and in which R1and Het have the meanings indicated above for formula (I), a Y denotes a leaving group, preferably in the presence of a base.

As the leaving group Y in accordance with the described technology may be considered, for example, halogen, preferably chlorine, bromine or iodine, especially chlorine, or esters of sulfonic acids, such as esters of alkylsulfonic, mesilate or toilet.

Option b) of the method can be carried out preferably at normal or slightly elevated pressure and preferably in the presence of an aprotic solvent or diluent. As solvents, respectively, of suitable diluents, for example, ethers, and compounds of the type ethers, such as diethyl ether, DIPROPYLENE ether, disutility ether, dioxane, dimethoxyethane and tetrahydrofuran; aliphatic, aromatic and halogenated hydrocarbons, especially benzene, toluene, xylene, chloroform, methylene chloride, carbon tetrachloride and chlorobenzene; NITRILES, such as acetonitrile or propionitrile; dimethyl sulfoxide or dimethylformamide, and mixtures of these solvents. This variant of the method is carried out usually at temperatures in the range -20 to +140oC, preferably from 0 I, such as sodium carbonate and potassium. As grounds for this purpose can be used and hydrides, such as sodium hydride, potassium hydride and calcium hydride. If necessary, the reaction can be carried out also in the presence of a catalyst, such as cesium chloride.

Another object of the invention is
C) the method of producing compounds of formulas (IIIa) and (IIIb), which is characterized by the fact that either the compound of the formula
H2N-A-NH2(Va),
or a compound of the formula

and not necessarily their E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in free form or in the form of salts, in which a and U have the same values as above for compounds of formulas (IIA) and (IIb), and which are known or can be obtained analogously to known methods, in the case of obtaining the compounds of formula (IIIa) is subjected to interaction with two equivalents, and in the case of obtaining the compounds of formula (IIIb) with three equivalents of the compounds of formula

which is known or can be obtained analogously to known methods and in which R2has the same meaning as indicated for formula (I), in the presence of excess formaldehyde or paraform and, but under certain conditions and at elevated pressure, in an inert solvent and at temperatures in the range from 0 to +140oC, preferably from +20 to +120oC. as solvents most suitable alcohols, such as methanol, ethanol and propanol, and water. Besides the above-mentioned solvents are suitable, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and chlorobenzene, or other solvents that do not influence the reaction of the negative impacts. All solvents can also be used in the form of their mixtures. In some cases it is advisable to work with the addition of an acid catalyst, such as Hcl, H2SO4or with the addition of sulfonic acids such as p-toluensulfonate. Formed during the reaction water can be removed with water separator or by adding molecular sieves.

Another object of the invention is
g) the method of obtaining the compounds of formula (I), which differs in that the compound of formula (Va) or formula (Vb) interaction with connection forms the Ib), after which the compound of formula (IIIa) or (IIIb) with the compounds of formula (IV) is transferred to the compound of formula (IIA) or (IIb) and at the completion of this compound of formula (IIA) or (IIb) hydrolyzing.

Other objects of the present invention are compounds of formula (IIA), (IIb), (IIIA) and (IIIb) and do not necessarily their E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in free form or in the form of salts, and their use for producing compounds of formula (I).

The most preferred embodiments of the method according to b)-d) is explained in detail in the examples.

Obtained according to the invention the compounds of formula (I) are known. Having good compatibility with respect to warm-blooded animals, fish and plants, they are valuable active substances which can be used for pest control. First of all compounds of formula I are suitable for effectively combating insects and arachnids affecting the useful and ornamental plants in agriculture, particularly cotton, vegetable and fruit growing, forestry, to protect stocks and materials, as well as in the field of hygiene, primarily on domestic and useful animals. These compounds are effective primarily in terms of their
Example H1.1: Obtain the compounds of formula

A mixture of 3.0 g of 1-methyl-2-nitroguanidine, 0.85 grams of 1,2-diaminoethane, 15 ml of dioxane and 5.7 ml of a 37% solution of formaldehyde in water is heated at room temperature to 50oWith and within 4 hours and stirred at this temperature. The mixture is then evaporated to dryness under vacuum, the residue is thoroughly mixed with diethyl ether and indicated in the title compound allocate by filtration, tPL222-223o(Compound 1.1).

Example H1.2: Obtain the compounds of formula

A mixture of 1.8 g of 1-methyl-2-nitroguanidine, 1.35 g of paraformaldehyde and 0.78 g of 1,5-diamino-3-oxapentane in 20 ml toluene and 20 ml of dioxane is mixed at room temperature with two drops of 37% aqueous solution of model HC1 in water, then heated to a temperature of reflux distilled and stirred for 6 hours at this temperature. After that, the mixture is evaporated to dryness under vacuum, the residue is thoroughly mixed with diethyl ether and filtered by allocate specified in the header of the connection (connection 1.15).

Example H1.3: Obtain the compounds of formula

A mixture of 8.0 g of 1-methyl-2-nitroguanidine and 3.0 g of diaminobutane in 25 ml of ethane is within 16 hours and stirred at this temperature. The mixture is then evaporated to dryness under vacuum and the residue is thoroughly mixed with ethanol. In this way receive specified in the header of the connection with tPL232-234o(Compound 1.4).

Example H1.4: Obtain the compounds of formula

A mixture of 6.0 g of 1-methyl-2-nitroguanidine and 5.4 g of 4,9-dioxa-1,12-diaminododecane in 25 ml of ethanol is mixed at room temperature with 19 ml of a 37% solution of formaldehyde in water, heated to 50oWith and stirred for 16 hours at this temperature. The mixture is then cooled to 5oC, filtered and the residue washed with a small amount of ethanol. In this way receive specified in the header of the connection with tPL140-143o(Connection 1.14).

Example H1.5: technology, similar to that described in examples H1.1-N1.4, can be obtained the compounds shown in table 1.

Example H2.1: Obtain the compounds of formula

A mixture of 2.4 g of 1-methyl-2-nitroguanidine and 1.0 g of Tris(2-amino-ethyl)amine in 50 ml of ethanol is mixed with 30 ml of 37% solution of formaldehyde in water, heated to 50oC and stirred for 16 hours at this temperature. The mixture is then evaporated to dryness under vacuum, the residue is carefully smeshivanie the title compound (compound 2.1).

Example H2.2: technology, similar to that described in example H2.1, can be obtained the compounds shown in table 2.

Example H3.1: Obtain the compounds of formula

A mixture of 2.0 g obtained according to example H1.1 product, 1.6 g of 2-chloro-5-chloromethylpyridine and 2.8 g of potassium carbonate in 20 ml of dimethylformamide is stirred for 9 hours at 90oC. Then the reaction mixture is filtered, the filtrate is evaporated under vacuum and the residue is dissolved in 100 ml of dichloromethane. The organic phase is washed with 50 ml water and 50 ml saturated sodium chloride solution, dried over MgSO4and evaporated to dryness. The residue is thoroughly mixed with diethyl ether and indicated in the title compound allocate by filtering (compound 10.B.1).

Example H3.2: Obtain the compounds of formula

A mixture of 3.7 g obtained according to example H1.3 connections, 3.2 g of 2-chloro-5-chloromethylpyridine and 5.5 g of potassium carbonate in 20 ml of dimethylformamide is stirred for 16 hours at 55oC. Then the reaction mixture is filtered, the filtrate evaporated under vacuum, the residue is thoroughly mixed with methanol and filtered. In this way receive specified in the header of the connection with tPL
A mixture of 4.9 g obtained according to example H1.4 connections, 3,24 g of 2-chloro-5-chloromethylpyridine and 5.5 g of potassium carbonate in 20 ml of dimethylformamide is stirred for 16 hours at 55oC. Then the reaction mixture is filtered, the filtrate is evaporated under vacuum and the residue purified on silica gel using methyl ester of acetic acid/methanol (ratio 2:1) as eluents. In this way receive specified in the header of the connection with tPL70-72o(Compound 10.In.14).

Example H3.4: Obtain the compounds of formula

A mixture of 2.0 g obtained according to example H1.1 connection of 1.95 g of 2-chloro-5-chloromethylthiazole, 4.0 g of potassium carbonate and 1.53 g of 18-crown-6 (1,5,7,10,13,16-hexaoxacyclooctadecane) in 20 ml of tetrahydrofuran is stirred for 24 hours at 50oC. Then the reaction mixture is filtered, the filtrate is evaporated under vacuum and the residue purified on silica gel using dichloromethane/methanol (ratio 9:1) as eluents. In this way receive specified in the header of the connection with tPL175-178o(Compound 3.In.1).

Example H3.5: technology, similar to that described in examples N3.1-H3.4, can be obtained the compounds shown in tables 3-26.

Tabulate value specified in the corresponding table row Century.

The connection 3.In.01: tPL175-178oC.

Table 4: compounds of General formula (IIc), where Het means

and has in every case the value specified in the corresponding table row Century.

Table 5: compounds of General formula (IIc), where Het means

and has in every case the value specified in the corresponding table row Century.

Table 6: compounds of General formula (IIc), where Het means

and has in every case the value specified in the corresponding table row Century.

Table 7: compounds of General formula (IIc), where Het denotes 2-methyltetrahydrofuran-4-yl, and has in each case the value specified in the corresponding table row Century.

Table 8: compounds of General formula (IIc), where Het means tetraboron-3-yl, and has in each case the value specified in the corresponding table row Century.

Table 9: compounds of General formula (IIc), where Het means

and has in every case the value specified in the corresponding table row Century.

Table 10: compounds of General formula (IIc), where Het hereafter the rock table Century.

The connection 10.In.04: tPL178-180oC.

The connection 10.In.14: tPL70-72oC.

Table 11: compounds of General formula (IIc), where et means of pyrid-3-yl, and has in each case the value specified in the corresponding table row Century.

Table 12: compounds of General formula (IIc), where Het means

and has in every case the value specified in the corresponding table row Century.

Table 13: compounds of General formula (IIc), where Het means

and has in every case the value specified in the corresponding table row Century.

Table 14: compounds of General formula (IIc), where Het represents 2,3-dichloride-5-yl, and has in each case the value specified in the corresponding table row Century.

Table 15: compounds of General formula (IId), where Het means

and A1And2And3and X in each case have the meanings specified in the corresponding line of the table C.

Table 16: compounds of General formula (IId), where Het means

and A1And2And3and X in each case have the meanings specified in the corresponding line of the table C.

Table And3and X in each case have the meanings specified in the corresponding line of the table C.

Table 18: compounds of General formula (IId), where Het means

and A1And2And3and X in each case have the meanings specified in the corresponding line of the table C.

Table 19: compounds of General formula (IId), where Het denotes 2-methyltetrahydrofuran-4-yl, and A1And2And3and X in each case have the meanings specified in the corresponding line of the table C.

Table 20: compounds of General formula (IId), where Het represents 3-tetrahydrofuranyl, and A1And2And3and X in each case have the meanings specified in the corresponding line of the table C.

Table 21: compounds of General formula (IId), where Het means

and A1And2And3and X in each case have the meanings specified in the corresponding line of the table C.

Table 22: compounds of General formula (IId), where Het denotes 2-chloropyrid-5-yl, a a1And2And3and X in each case have the meanings specified in the corresponding line of the table C.

Table 23: compounds of General formula (IId), where Het represents 3-pyridyl, a a1And2And3and X in carmoly (IId), where Het means

and A1And2And3and X in each case have the meanings specified in the corresponding line of the table C.

Table 25: compounds of General formula (IId), where Het means

a a1And2And3and X in each case have the meanings specified in the corresponding line of the table C.

Table 26: compounds of General formula (IId), where Het represents 2,3-dichloride-5-yl, and A1And2And3and X in each case have the meanings specified in the corresponding line of the table C.

Example H4.1: Obtain the compounds of formula

1.2 g obtained according to example H3.1 connection is stirred together with 10 ml of methanol and 10 ml of 1 N. hydrochloric acid for 16 hours at room temperature. Then the reaction mixture is evaporated to dryness and the residue purified on silica gel using dichloromethane/methanol (ratio 95:5) as eluents. In this way receive specified in the header of the product with tPL147-149o(Connection 27.6).

Example H4.2: Obtain the compounds of formula

1.2 g obtained according to example H3.4 connections stirred somewhat to dryness and the residue recrystallization from methanol. In this way receive specified in the header of the product with tPL170-172oC (connection 27.1).

Example H4.3: technology, similar to that described in examples N4.1 and H4.2, can be obtained the compounds shown in table 27.

Another object of the invention is a method of combating pests, especially insects and representatives of the order of mites, with compounds of the formulas (IIA) and (IIb). To these pests include in particular those which are specified in European application EP 736252. So stated in this proposal pests included as references in the scope of the present invention. In the above-mentioned application also described ways of dealing with these pests, as well as the composition and receipt of the relevant funds, and they are also included as references in the scope of the present invention.


Claims

1. The method of obtaining substituted derivatives of 2-nitroguanidine formula

and not necessarily its E/Z-Izmerov, mixtures of E/Z-isomers and/or tautomers, in free form or in the form of salts,
where
R1denotes hydrogen or C1-C4alkyl;
R2denotes hydrogen, C1-C6the dependence of the possibilities for substitution in the ring system is from one - to five-fold substituted by substituents selected from the group comprising halogen, C1-C3alkyl, C1-C3alkoxy, halogen-C1-C3alkyl, C1-C3halogenoalkane, cyclopropyl, halogenlampen,2-C3alkenyl,2-C3quinil,2-C3halogenoalkanes,2-C3halogenoalkanes,1-C3alkylthio,1-C3allogenicity, allyloxy, propargyloxy, allylthio, propargite, halogenations, halogenierte, cyan and nitro, aromatic or non-aromatic, monocyclic or bicyclic heterocyclic residue;
In denotes phenyl, 3-pyridyl or thiazolyl, optionally substituted with one to three substituents selected from the group comprising From1-C3alkyl, C1-C3halogenated, cyclopropyl, halogenlampen,2-C3ekenel,2-C3quinil,1-C3alkoxy, C2-C3halogenoalkanes,2-C3halogenoalkanes,1-C3halogenoalkane,1-C3alkylthio,1-C3allogenicity, allyloxy, propargyloxy, allylthio, propargite, halogenations, halogenierte, halogen, CYANOGEN Ipotechniy or branched C2-C20alkylen,2-C20albaniles,2-C20akinyan,3-C12cycloalkyl, Allen or heterocyclyl, and group C2-C20alkylen,2-C20albaniles,2-C20akinyan,3-C12cycloalkyl, Allen and heterocyclyl optional one - or many times independently from each other substituted and group2-C20alkylen,2-C20albaniles and C2-C20akinyan optionally independently of one another one or repeatedly broken O, N-H or N-C1-C12the alkyl, C3-C9cycloalkenes, aryleno or heterocyclisation or means a group-D1-D2-D3- where D1and D3independently of one another denote an optionally substituted C3-C12cycloalkyl or Allen, and D2stands With2-C20alkylen,2-C20albaniles,2-C20akinyan, O, N-H or N-C1-C12alkyl;
Q is a

a R1, R2and Het have the meanings indicated above for formula (I),
and not necessarily its E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in free form or in VI is the I, the compounds of formula (I) are obtained in free form.

3. The method according to p. 1 or 2, wherein R1denotes hydrogen.

4. The method according to any of paragraphs.1-3, wherein R2denotes hydrogen, C1-C3alkyl or cyclopropyl.

5. The method according to any of paragraphs.1-4, wherein Het denotes 2-chloropyrid-5-yl, tetrahydrofuran-3-yl, 5-methyltetrahydrofuran-3-yl or 2-chlorothiazole-5-yl.

6. The method according to any of paragraphs.1-5, characterized in that the hydrolysis is carried out in water, alcohol or a mixture of water and alcohol.

7. The method of obtaining the compounds of formula
Q-A-Q, (IIA),
where a matter specified in paragraph 1 for formula (IIA);
Q is a

where R1, R2and Het have the meanings specified in paragraph 1 for formula (I),
and not necessarily its E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in free form or in the form of salts, characterized in that the compound of the formula
T-a-T, (IIIA)
where a has the same meaning as indicated for formula (IIA), and T is a

where R2has the same meaning as specified in paragraph 1 for formula (I),
and not necessarily its E/Z-isomers, mixtures of E/Z-isomers and/or tautomerase formula

where R1and Het have the meanings specified in paragraph 1 for formula (I), a Y denotes a leaving group.

8. The method of obtaining the compounds of formula (IIIa) described in paragraph 7, characterized in that the compound of the formula
H2N-A-NH2(Va),
and not necessarily its E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in free form or in the form of salts, where a has the same meaning as specified in paragraph 1 for the compounds of formula (IIA), is subjected to the interaction with two equivalents of the compounds of formula

where R2has the same meaning as indicated for formula (I),
in the presence of excess formaldehyde or paraformaldehyde.

 

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< / BR>
where R1- H, C1-C6alkyl; phenyl, possibly substituted; biphenyl, possibly substituted; 1H, 5H - pyrido [3,2,1-ij] chinolin; phenyl WITH1-C6alkyl, optionally substituted; biphenyl WITH1-C6alkyl, optionally substituted; biphenylcarboxylic; terphenyl; naphthyl, optionally substituted; Z denotes-S-, -O-, -och2-, -N(R16), where R16- H, C1-C6alkyl, C3-C8cycloalkyl1-C6alkyl, panels1-C6alkyl, a chemical bond; X1means-CO-, -(CH2)r-CO-N(R17), where R17means H, C1-C6alkyl (where r = 0 or 1), -CH2NHSO2-, -(CH2)s-N (R18)-CO- (where R18- N, s=1-3), - CH2NHCОСН2O-, -CH2N (R19Of PINES = CH- (where R19- H, -CH2OCH2-, -CH2-N (R20)-CH2- (where R20- H, C1-C6alkyl, C1-C6alkylsulphonyl, phenylcarbinol)1-C5alkylen,2-C4albaniles, a chemical bond; X2- phenylene, optionally substituted hydroxy, theoffender, purandar, piperidinyl,< / BR>
< / BR>
< / BR>
R2and R3each - H; and R4- phenyl, possibly substituted with halogen; R5- phenyl, possibly substituted; a cycle of G is phenyl,3-C7cycloalkyl, pyridyl, thienyl; loop J is phenyl; L is phenyl; p=0-2;----- means the presence or absence of chemical bonding;displays a CIS - or TRANS-configuration D relative to E; provided that X1means-CH2NHCО-, X2means 1,4-phenylene and X3means a chemical bond or a C1-C5alkylen, when the carbon atom bound CD and adjacent carbon atom in the cycle are connected by a simple relation and V1does not mean a chemical bond, when X1means-CH2O-; and pharmaceutically acceptable salt or hydrate of the compound

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< / BR>
where G1- CH2; G2- C(O); m = 2 or 3, n is 0 or 1; R1is 1-3 substituent, independently selected from H, G, C1-C6alkoxy; R2is 1-3 substituent, independently selected from H, C1-C6alkoxy; R3means N or

< / BR>
< / BR>
< / BR>
R4- H; Ar1means

< / BR>
< / BR>
R8means 1-3 substituent, independently selected from H, G; R9means N;

And means

< / BR>
< / BR>
< / BR>
where p = 1, 2, 3, or 4; X is-O-, -CH2-; R10-H, C1-C6alkyl or

< / BR>
">< / BR>
< / BR>
< / BR>
where q = 2 or 3; R5- C1-C4alkyl, (CH2)2HE; R6- C1-C4alkyl, -(CH2)2HE, (CH2)2N(CH3)2; R5', R6' - C1-C4alkyl; R7- C1-C6alkyl, and the stereoisomers and pharmaceutically acceptable salts

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