EA009517B1

EA009517B1 - Pyrazolopyrimidines

Info

Publication number: EA009517B1
Application number: EA200600021A
Authority: EA
Inventors: Олаф Гебауэр; Ульрих Хайнеман; Штефан Херрманн; Оливер Гут; Ханс-Людвиг Эльбе; Херберт Гайер; Йорг Нико Гройль; Штефан Хиллебранд; Рональд Эбберт; Ульрике Вахендорф-Нойман; Петер Дамен; Карл-Хайнц Кук
Original assignee: Байер Кропсайенс Аг
Priority date: 2003-06-27
Filing date: 2004-06-18
Publication date: 2008-02-28
Also published as: ECSP056252A; IL172592A0; EA200600021A1

Abstract

The invention relates to the novel pyrazolopyrimidines of formula (I),wherein R, R, R, R, X and Hal are defined as in the description, to several method for producing said substances and to their use for controlling undesired microorganisms.The invention also relates to the novel intermediates of the formulae (II) (X) (XII-a) and (XII-b)and to methods for producing said substances.

Description

This invention relates to nitrogen-containing heterocyclic compounds with biological activity, more specifically to new pyrazolopyrimidines, to a method for their production, their use for combating unwanted microorganisms, new intermediate compounds and methods for their preparation.

Certain pyrazolopyrimidines are known to have fungicidal properties (see-3130633 or ЕК-А 2794745). The effectiveness of these substances is good, however, with small quantities used in some cases insufficient.

The objective of the invention is the development of new pyrazolopyrimidines, which can be successfully used to combat unwanted microorganisms.

The problem is solved by the proposed pyrazolopyrimidine formula (I)

where K ¹ means alkyl containing 1-6 carbon atoms, which can be substituted from one to five times, the same or different by halogen, cyano, hydroxy, alkoxygroup containing 1-4 carbon atoms, and / or cycloalkyl containing 3- 6 carbon atoms, or

K ¹ means alkenyl containing 2-6 carbon atoms, which can be substituted from one to three times, the same or different by halogen, cyano, hydroxy, alkoxy group containing 14 carbon atoms, and / or cycloalkyl containing 3-6 carbon atoms , or

K ¹ means cycloalkyl containing 3-6 carbon atoms, which can be substituted from one to three times, the same or different by halogen and / or alkyl, containing 1-4 carbon atoms,

K ² means hydrogen or alkyl containing 1-4 carbon atoms, or

K ¹ and K ^2, together with the nitrogen atom to which they are attached, means a saturated or unsaturated heterocyclic ring containing 3-6 atoms in the ring, and the heterocycle may additionally contain a nitrogen, oxygen or sulfur atom as a ring atom and may be substituted to three times fluorine, chlorine, bromine, alkyl containing 1-4 carbon atoms, and / or haloalkyl containing 1-4 carbon atoms and 1-9 fluorine and / or chlorine atoms,

K ³ means a saturated or unsaturated heterocyclyl containing 5 or 6 atoms in the ring and 1-4 heteroatoms, such as nitrogen and / or sulfur, and heterocyclyl can be substituted from one to four times, the same or different by fluorine, chlorine, bromine, cyano , nitro, alkyl, alkoxy, hydroxyiminoalkyl or alkoxyiminoalkyl with 1-3 carbon atoms in each alkyl part, haloalkyl or haloalkoxy group containing 1-3 carbon atoms and 1-7 halo atoms,

K ⁴ means hydrogen,

1 means fluorine, chlorine or bromine and

X means cyano, fluorine, chlorine, bromine, iodine, formyl, alkenyl containing 2-6 carbon atoms, alkenyl containing 2-5 carbon atoms in the alkenyl part and substituted by carboxy group, methoxycarbonyl or ethoxycarbonyl, alkoxycarbonyl containing 1-4 atoms in alkoxy part.

Preferred pyrazolopyrimidines of formula (I) are compounds in which

K ¹ means a radical of the formula

and # means the place of accession,

- 1 009517

In ² means hydrogen, methyl, ethyl or propyl or

B ¹ and B ² together with the nitrogen atom to which they are attached mean pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 3,6-dihydro-1 (2H) -piperidinyl or tetrahydro-1 (2H) pyridazinyl, and these radicals may be substituted by 1-3 fluorine atoms, 1-3 methyl groups and / or trifluoromethyl, or

B ¹ and B ^2, together with the nitrogen atom to which they are attached, mean a radical of the formula

where B 'means hydrogen or methyl,

B means methyl, ethyl, fluorine, chlorine or trifluoromethyl, t means numbers 0, 1, 2 or 3, moreover B means the same or different radicals, if t means 2 or 3,

B ′ means methyl, ethyl, fluorine, chlorine or trifluoromethyl and n means 0, 1, 2 or 3, and B ′ means identical or different radicals, if η means 2 or 3,

³ means pyridyl, which is attached at the 2- or 4-position and can be substituted from one to four times, in the same or different way by fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, methoxy, methylthio, hydroxymyminomethyl, hydroxyiminoethyl, methoxyminomethyl, methoxyminoethyl and / or trifluoromethyl, or

B ³ means pyrimidyl, which is attached at the 2- or 4-position and can be substituted from one to three times, in the same or different way by fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, methoxy, methylthio, hydroxyimomethyl, hydroxyiminoethyl, methoxyminomethyl, methoxyminoethyl and / or trifluoromethyl, or

B ³ means thienyl, which is attached at the 2- or 3-position and can be substituted from one to three times, in the same or different way by fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, methoxy, methylthio, hydroxymeminomethyl, hydroximinoethyl, methoxyminomethyl, methoxyminoethyl and / or trifluoromethyl, or

⁴ means hydrogen,

Na1 means fluorine or chlorine and

X means cyano, fluorine, chlorine, bromine, iodine, formyl or methoxycarbonyl, or

X is a radical of formula -CH = CH _2, - <r _g = CH, -CH-CH-CH ₃ CH, CH, -CH = CH-N with ₅ _g CH-C ₂ H ₅ -CH = CH-COOH

CH, —CH = CH — CO — OCH, or — CH = CH — CO — OC ₂ H ₅ .

Depending on the position of the substituents, the compounds according to the invention may, if necessary, be represented as mixtures of various possible isomeric forms, in particular stereoisomers, such as E- and Ζ-, threo and erythro, and optical isomers, if necessary also in the form tautomers. If B ^{3 is} unequally substituted on both atoms adjacent to the point of attachment, then the corresponding compounds can be represented in a special form of stereoisomers, and, moreover, atropisomers.

The pyrazolopyrimidines of the above formula (I) are obtained due to the fact that the halopyrazolopyrimidines of the formula kNaH where B ⁴ and H1 have the above values,

³ means pyridyl, which is attached at the 2- or 4-position and can be substituted from once to four times by trifluoromethyl, or

- 2 009517

I ³ means pyrimidyl, which is attached at the 2- or 4-position and can be substituted from one to three times, equally or differently by fluorine and / or chlorine,

I ³ means thienyl, which is attached at the 2- or 3-position and can be substituted from one to three times by chlorine or methyl, X ¹ means a cyano group or formyl, and Υ ¹ means halogen, is reacted with amines of the formula

where I ¹ and I ² have the above values, if necessary in the presence of a diluent, if necessary in the presence of an acid acceptor and if necessary in the presence of a catalyst.

This method, which is referred to below as method a), is an object of the invention. The pyrazolopyrimidines of the above formula (I) can also be obtained due to the fact that b) the pyrazolopyrimidines of the formula

where I ¹ , I ² , I ³ , I ⁴ and Na1 have the meanings given above, interact or

a) with diisobutyl aluminum hydride in the presence of an aqueous solution of ammonium chloride, as well as in the presence of an organic diluent, or

β) with the Grignard compounds of the formula K ⁵ - MD - X ² (IV), where I ⁵ means alkyl and

X ² means chlorine or bromine, in the presence of a diluent and, if necessary, in the presence of a catalyst, or c) pyrazolopyrimidines of the formula

where I ¹ , I ² , I ³ , I ⁴ and Na1 have the meanings given above, and

I ⁶ means hydrogen or alkyl, is reacted or α) with amino compounds of the formula η ₂ ν-οκ ⁷ where I ⁷ means hydrogen or alkyl, in the presence of a diluent and, if necessary, in the presence of a catalyst, and the amino compounds of formula (V) can also be used as their addition salts with an acid, or

β) with triphenylphosphonium salts of the formula

where Ry means phenyl and

I ⁸ means hydrogen or not substituted or substituted alkyl, in the presence of a base, and also in the presence of a diluent, or

γ) with diisobutyl aluminum hydride in the presence of an aqueous solution of ammonium chloride, as well as in the presence of an organic diluent, or with sodium borohydride in the presence of a diluent, and if necessary the resulting pyrazolopyrimidines of the formula

where I ¹ , I ² , I ³ , I ⁴ , I ⁸ and Na1 have the meanings given above, are reacted with alkylating agents of the formula

- 3 009517

where K ⁹ means alkyl and

X ³ means chlorine, bromine, iodine or the radical K ⁹ 0-80 ₂ -0-, if necessary in the presence of a base and in the presence of a diluent, or

b) pyrazolopyrimidines of the formula

where K ¹ , K ² , K ³ , K ⁴ and Na1 have the meanings given above,

K ¹⁰ is hydrogen, either unsubstituted or substituted alkyl, is reacted with strong bases in the presence of a diluent, or

e) pyrazolopyrimidines of the formula

where K ¹ , K ² , K ³ , K ⁴ and Na have the meanings given above, are reacted with acyl derivatives of the formula

where K ¹¹ means alkyl and

X ⁴ means chlorine or a radical of formula

in the presence of a catalyst and in the presence of a diluent.

The pyrazolopyrimidines of formula (I) are very well suited for controlling unwanted microorganisms. They show primarily strong fungicidal efficacy and can be applied both in plant protection and in the protection of materials.

It was unexpectedly found that the pyrazolopyrimidines of the formula (I) have significantly better microbicidal efficacy compared to previously known substances of the same direction of action similar in structure.

The compounds of formula (I) according to this invention, if necessary, can be represented as mixtures of various isomeric forms, in particular stereoisomers, such as E- and Ζ-, threo- and erythro, and also optical isomers, such as K-and 8- isomers or atropisomers, if necessary, also in the form of tautomers.

Both the pure stereoisomers and any mixtures of these isomers are the subject of this invention, even if at all here we are talking only about compounds of the formula (I).

Depending on the type of the above substituents, the compounds of formula (I) exhibit acidic or basic properties and can form salts. If the compounds of formula (I) contain hydroxy, carboxy or other groups that cause acidic properties, then these compounds can be converted into salts with bases. Suitable bases are, for example, hydroxides, carbonates, hydrogen carbonates of alkali and alkaline earth metals, in particular, sodium, potassium, magnesium and calcium, in addition, ammonia, primary, secondary and tertiary amines with (C ₁ -C ₄ ) -alkyl radicals, as well as mono-, di- and trialkanolamines (C ₁ -C ₄ ) -alkanols. If the compounds of formula (I) contain amino, alkylamino, or other groups that cause basic properties, these compounds can be converted into salts with the help of acids. Suitable acids are, for example, mineral acids, such as hydrochloric, sulfuric, and phosphoric acid, organic acids, such as acetic or oxalic acid, and acidic salts, such as αΗ80 ₄ and KH§0 ₄ . The salts thus obtained also exhibit fungicidal and microbicidal properties.

Also included in the scope of the invention are salt-like derivatives, which are obtained from compounds of formula (I) by reacting with the basic, respectively, with acidic compounds, as well as Ν oxides obtained by conventional oxygenation methods.

If 3-cyano-5,7-dichloro-6- (3-trifluoromethylpyridin-2yl) pyrazolo [1,5-a] pyrimidine and 2,2,2-trifluoroisopropylamine are used as starting materials, the implementation of method (a) according to This invention can be visualized in the form of the following scheme.

- 4 009517

If 3-cyano-5-chloro-6- (3-trifluoromethylpyridin-2-yl) 7- (2,2,2-trifluoroisopropylamino) pyrazolo [1,5-a] pyrimidine is used as the starting material, and as the reaction component diisobutylaluminum hydride is used, the implementation of method (b) (variant α) can be clearly described

If 3-cyano-5-chloro-6- (3-trifluoromethylpyridin-2-yl) 7- (2,2,2-trifluoroisopropylamino) pyrazolo [1,5-a] pyrimidine is used as the starting material, and as the reaction component using methylmagnesium bromide, the implementation of method (b) (option β) can be visualized in

If 3-formyl-5-chloro-4- (3-trifluoromethylpyridin-2-yl) 7- (2,2,2-trifluoroisopropylamino) pyrazolo [1,5a] pyrimidine hydrochloride and methoxyamine hydrochloride are used as starting materials, the method (c) (option α) can be visualized in the form of the following scheme.

_? and ₃

SSS

sn = s-osn ₃

If 3-methylcarbonyl-5-chloro-6- (3-trifluoromethylpyridin-2-yl) -7- (2,2,2-trifluoroisopropylamino) pyrazolo [1,5a] pyrimidine is used as the starting material, and as the reaction component, triphenylmethylphosphonium bromide, the implementation of method (c) (option β) can be visualized in the form of the following scheme.

- 5 009517

If 3-methylcarbonyl-5-chloro-6- (3-trifluoromethyl-pyridin-2-yl) -7- (2,2,2-trifluoro-isopropylamino) pyrazolo [1,5a] pyrimidine is used as the starting material, and diisobutylaluminum hydride in the first stage and methyl iodide in the second stage, the implementation of method (c) (variant γ) can be visualized as the following scheme.

substances use

If as the source

- (1,2-dibromopropyl) -5-chloro-6- (5chloropyrimidin-4-yl) -7- (4-methylpiperidino) pyrazolo [1.5a] pyrimidine and potassium tert-butylate are used as the reaction component, then method (b) can be visualized in the form of the following scheme.

the original substance is used

If in quality

-chloro-6- (5-chloropyrimidine-4 -yl) -7- (4methylpiperidino) pyrazolo [1,5a] pyrimidine, acetyl chloride is used as the reaction component and aluminum trichloride is used as a catalyst, method (e) can be clearly present in the form of the following scheme.

The halopypyrazolopyrimidines of formula (II) are new compounds. These substances are also suitable for controlling unwanted microorganisms.

Halo-pyrazolopyrimidines of formula (II) can be obtained if ί) hydroxypyrazole pyrimidines of formula

where I ³ and I ⁴ have the meanings given above, and

I means cyano or alkoxycarbonyl containing 1-4 carbon atoms in the alkoxy part, is reacted with halogenating agents, if necessary in the presence of

- 6 009517 diluent, or, if X ¹ means formyl, d) hydroxypyrazolopyrimidine formula

where B ³ and B ⁴ have the meanings given above, are reacted with phosphorous oxychloride in the presence of dimethylformamide and, if necessary, with the addition of phosphorus pentachloride, continue the interaction.

If 3-cyano-6- (3-trifluoromethylpyridin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol is used as the starting material, and phosphoroxychloride in the mixture with phosphorus pentachloride is used as the halogenating agent, The implementation of the method (ί) can be visualized in the form of the following scheme.

The hydroxypyrazolopyrimidines of formula (X) have also not been known to date. They can be obtained if (th) heterocyclylmalonate of the formula

COOK ¹² * ^E - ((XII),

SOOK ¹² where B ³ has the meanings given above and

In ¹² means alkyl containing 1-4 carbon atoms, is subjected to interaction with aminopyrazole formula

where B ⁴ and B have the meanings given above, if necessary in the presence of a diluent and if necessary in the presence of an acid binding agent.

If 2- (3-trifluoromethylpyridin-2yl) -malonic acid and 3-amino-4-cyanopyrazole dimethyl ether and 3-amino-4-cyanopyrazole are used as starting materials, the implementation of method (s) can be visualized as follows.

The heterocyclylmalone esters of formula (XII) are partially known (see ΌΕ 3820538-A, © O 0111965, and © O 99-32464).

New are pyridylmalonate formula

SOOK ¹²

COOK ¹² (XII-a), K ¹³ where B ¹² means alkyl containing 1-4 carbon atoms, and B ¹³ means haloalkyl containing 1-4 carbon atoms. New are pyrimidyl ether formulas

- 7 009517 I '\

COOH ¹² (ΧΙΙ-Ь),

COOH ¹² n '° n ¹⁴ where K ¹² has the meaning given above,

K means halogen, and

K ¹⁵ and K ¹⁶ each means hydrogen.

Pyridylmalonate esters of formula (X11-a) can be obtained if (1) halopyridines of formula

(Xv) where K ¹³ has the meaning given above, and

Υ ² means halogen, subjected to interaction with malonic esters of the formula

COOH ¹²

COOH ¹² where K ¹² has the meaning given above, if necessary in the presence of a diluent, if necessary in the presence of a copper salt, and if necessary in the presence of an acid acceptor.

If 2-chloro-3-trifluoromethylpyridine and malonic acid dimethyl ester are used as starting materials, the implementation of method (1) according to the invention can be visualized as the following scheme.

The halopyridines of formula (XIV) are known chemical reagents for synthesis.

Malonic esters of formula (XV), also used in the implementation of method (1) according to this invention, are also known chemical reagents for synthesis.

Pyrimidyl ethers of formula (A-b) can be obtained if ()) pyrimidines of formula

(Xv) where K ¹⁴ , K ¹⁵ and K ¹⁶ are as defined above, and

Υ ³ means halogen, is reacted with malonic esters of formula ^ soon ¹² soon ¹² where K ¹² has the meaning given above, if necessary in the presence of a diluent, if necessary in the presence of a copper salt and if necessary in the presence of an acid acceptor.

If 4,5-dichloropyrimidine and malonic acid dimethyl ester are used as starting materials, the implementation of the method ()) according to the invention can be visualized in the form of the following scheme.

The halopyrimidines used as starting materials in the process (|) according to the invention are described in general terms by formula (XVI). In this formula, the radical K. ¹⁴ preferably means fluorine, chlorine, Υ ³ preferably means chlorine or bromine.

The halopyrimidines of formula (XVI) are known compounds and can be obtained

- 8 009517 by known methods (see 1. SN. 8th. 1955, 3478, 3481).

Aminopyrazoles used as reaction components in the process (H) according to the invention are described in general form by formula (XIII). In this formula, the K ⁴ radical is preferably such values as are indicated in connection with the description of the substances of formula (I) according to this invention as preferred values for this radical. The radical K is preferably of such values as are given in connection with the description of the hydroxypyrazolopyrimidines of the formula (X) as preferred values for this radical.

Aminopyrazoles of formula (XIII) are known or can be obtained by known methods.

As the halogenating agent in the process (1), all the usual components are suitable for replacing hydroxyl groups with halides. Preferably, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, thionyl bromide or mixtures thereof can be used. The corresponding fluorine-containing compounds of the formula (II) can be obtained from chlorine or bromine-containing compounds by reacting with potassium fluoride.

These halogenating agents are known.

Method (e) is suitable for producing halo-pyrazolopyrimidines of the formula

It is clear where K ³ and K ⁴ have the meanings given above.

Hydroxypyrazolopyrimidines used as starting materials in the process (d) are described in general terms by formula (XI). In this formula, the K ³ and K ⁴ radicals preferably have values such that in connection with the description of the compounds of formula (I) according to this invention are indicated as preferred values for these radicals.

Hydroxypyrazolopyrimidines of the formula (XI) are obtained by the method (H), in which aminopyrazoles of the formula (XIII) are used, in which the radical K represents hydrogen.

Method (d) is carried out under the conditions of Vilsmeier formylation with phosphoroxychloride in the presence of dimethylformamide. You can also add phosphorus pentachloride as a chlorinating agent.

The temperature of the reactions in the implementation of the method (d) can vary in wide intervals. Generally work at temperatures from -10 to + 150 ° C, more preferably from 0 to 120 ° C.

In the implementation of the method (d) take on 1 mol of hydroxypyrazolopyrimidines of formula (XI) generally from 2 to 5 moles of dimethylformamide, from 5 to 15 moles of phosphoroxychloride and, if necessary, from 0 to 2 moles of phosphorus pentachloride. Processing is carried out in the usual ways.

The amines also used in carrying out the process (a) according to the invention are described in general terms by formula (III). In this formula, the K ¹ and K ² radicals preferably have values such that in connection with the description of the compounds of formula (I) according to this invention are indicated as preferred values for the K ¹ and K ² radicals.

The amines of formula (III) are known or can be obtained by known methods.

As diluents in the implementation of the method (a) according to this invention, all conventional inert organic solvents are suitable. Preferably, halogenated hydrocarbons are used, such as, for example, chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles, such as acetonitrile, propionitrile, n- or isobutyronitrile, or benzonitrile; amides, such as Ν, Ν-dimetiformamide, Ν,-dimethylacetamide, Ν-methylformanilide,-methylpyrrolidone or hexamethylphosphoric triamide; esters such as acetic acid methyl or ethyl ester; sulfoxides, such as dimethyl sulfoxide; sulfones, such as sulfolane.

As an acid acceptor in the implementation of the method (a) according to this invention, all inorganic or organic bases that are common for such interactions are suitable. Preferably, hydrides, hydroxides, amides, alcoholates, acetates, carbonates, or alkaline earth or alkali metal bicarbonates are used, for example sodium hydride, sodium amide, lithium diisopropylamide, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, acetate sodium, potassium acetate, calcium acetate, sodium carbonate, potassium carbonate, potassium bicarbonate and sodium bicarbonate, and, in addition, ammonium compounds, such as ammonium hydroxide, ammonium acetate and ammonium carbonate, as well as tertiary amines, such as trimethylamine, triethylamine, tributylamine, Ν, Ν-dimethylaniline, Ν, Ν-dimethylbenzylamine, pyridine, Ν-methylpiperidine, Ν-methylmorpholine, Ν, Ν-dimethylaminopyridine, diazabicyclooctane (ELVSO). diazabicyclonone (ΌΒΝ) or diazabicycloundecene (ΌΒυ).

As catalysts in the implementation of the method (a) according to this invention are suitable

- 9 009517 all reaction accelerators common for such interactions. Fluorides such as sodium fluoride, potassium fluoride or ammonium fluoride are preferably used.

The temperature of the reactions in the implementation of the method (a) according to this invention can vary over a wide range. Generally work at temperatures from 0 to 150 ° C, more preferably at temperatures from 0 to 80 ° C.

When carrying out the process (a) according to the invention, per mole of halopyrazolopyrimidine of formula (II) is generally from 0.5 to 10 moles, preferably from 0.8 to 2 moles of the amine of formula (III). Processing is carried out in the usual ways.

The pyrazolopyrimidines used as starting materials in the process (b) are described in general terms by the formula Yes). In this formula, the radicals K ¹ , B ² , B ³ , B ⁴ and H1 are preferably of such meanings that, in connection with the description of the compounds of formula (I) according to this invention, are indicated as preferred values for these radicals.

In the case of pyrazolopyrimidines of the formula Yes), substances according to this invention are meant, which can be obtained by method (a) according to this invention.

As diluents for carrying out process (b) (option β), all common inert, organic solvents are suitable. Aliphatic or aromatic halogenated hydrocarbons, such as toluene, dichloromethane, chloroform or carbon tetrachloride, are preferably used.

The temperature of the reactions in the implementation of method (b) (option α) can vary in a certain range. Generally work at temperatures from -80 to + 20 ° C, more preferably from -60 to + 10 ° C.

In carrying out method (b) (option α), per mole of pyrazolopyrimidine of the formula Yes) is taken in general an equivalent amount or also an excess, preferably from 1.1 to 1.2 mole of diisobutyl aluminum hydride and finally an excess of an aqueous solution of ammonium chloride is added. Processing is carried out in the usual ways. As a rule, it is done in such a way that the reaction mixture is acidified, the organic phase is separated, the aqueous phase is extracted with an organic solvent that is poorly miscible with water, the combined organic phases are washed, dried and the solvent is distilled off under reduced pressure.

The Grignard compounds used as reaction components in the implementation of method (b) (variant β) are described in general form by formula (IV). In this formula, the B ⁵ radical preferably means alkyl containing 1-4 carbon atoms, more preferably methyl or ethyl. X ² preferably means bromine.

As a catalyst in the implementation of method (b) (option P), all reaction accelerators suitable for this kind of Grignard reactions are suitable. Examples include potassium iodide and iodine.

As a diluent in the implementation of method (b) (option β), all inert organic solvents that are usual for such interactions are suitable. It is preferable to use ethers, such as diethyl ether, dioxane or tetrahydrofuran, along with this, use aromatic hydrocarbons, such as toluene, as well as mixtures of ethers and aromatic hydrocarbons, such as toluene / tetrahydrofuran.

The temperatures of the reactions in the implementation of method (b) (option β) can vary in a certain range. Generally work at temperatures from -20 to + 100 ° C, more preferably from 0 to 80 ° C.

When carrying out method (b) (option β), per mole of pyrazolopyrimidine of the formula Yes) is taken, as a rule, 2-3 mol of the Grignard compound of formula (IV). In conclusion, carry out water processing in the usual way.

The pyrazolopyrimidines used as starting materials in the implementation of method (c) are described in general form by formula (D). In this formula, the radicals B ¹ , B ² , B ³ , B ⁴ and H1 are preferably of such meanings that, in connection with the description of the substances of formula (I) according to this invention, are indicated as preferred values for these radicals. The radical B ⁶ preferably means hydrogen or alkyl containing 1-4 carbon atoms, more preferably means hydrogen, methyl or ethyl.

In the case of pyrazolopyrimidines of the formula DL), the substances according to this invention are meant that can be obtained by the method (b) according to this invention.

Amino compounds used as reaction components in the implementation of method (c) (variant α) are described in general form by formula (V). In this formula, the radical B ⁷ preferably means hydrogen or alkyl containing 1-4 carbon atoms, more preferably means hydrogen, methyl or ethyl.

As reaction components, acid addition salts are also meant, preferably hydrochloride addition salts of amino compounds of formula (V).

Both the amino compounds of formula (V) and their acid addition salts are known or can

- 10 009517 to be obtained by known methods.

As diluents in the implementation of the method (c) (option α), all common inert organic solvents are suitable. Preferably, alcohols such as methanol, ethanol, npropanol or isopropanol are used.

As catalysts in the implementation of method (c) (variant α), all reaction accelerators usual for such interactions are suitable. Preferably, acidic or basic catalysts are used, such as, for example, the basic ion exchanger sold under the name Amberlist A-21®.

The temperature of the reactions in the implementation of method (c) (option α) can vary in a certain range. Generally work at temperatures from 0 to 80 ° C, more preferably from 10 to 60 ° C.

When carrying out the process (c) (option α), per mole of pyrazolopyrimidine of formula (1b) is generally equivalent or excess, preferably from 1.1 to 1.5 moles of amino compound of formula (V) or its addition salt with acid. Processing is carried out in the usual ways. In general, it is done in such a way that the reaction mixture is filtered if necessary, then the solvent is distilled off and cleaned.

Triphenylphosphonium salts used as reaction components in the process (c) (option (3) are described in general form by formula (VI). In this formula, P11 is phenyl. The radical K ^{8 is} preferably hydrogen or alkyl containing 1-4 atoms carbon radicals, the alkyl radicals may be substituted by carboxyl, methoxycarbonyl or ethoxycarbonyl. Particularly preferably, K ⁸ is hydrogen, methyl or ethyl, the latter two radicals being replaced by carboxyl, methoxycarbonyl or ethoxycarbonyl scrap.

Triphenylphosphonium salts of the formula (VI) are known or can be obtained by known methods.

As bases for the implementation of method (c) (variant β) according to the present invention, all deprotonating agents customary for such Wittig reactions are suitable. Butyllithium is preferably used.

As a diluent in the implementation of the method (c) (option β), all organic solvents customary for such Wittig reactions are suitable. Preferably, ethers such as dioxane and tetrahydrofuran are used.

The temperature of the reactions in the implementation of method (c) (option β) can be varied in a certain range. Generally work at temperatures from -78 to + 30 ° C.

In the implementation of method (c) (option β), per mole of pyrazolopyrimidine of formula (k) is taken an equivalent amount or an excess of triphenylphosphonium salt of formula (VI), as well as an equivalent amount or excess of base. Processing is carried out in the usual ways.

Alkylating agents used as reaction components in the implementation of method (c) (variant γ) are described by the general formula (VII). In this formula, the radical K ⁹ preferably means alkyl containing 1-4 carbon atoms, more preferably means methyl or ethyl. X ³ preferably means chlorine, bromine, iodine or the radical K ⁹ -O-8O ₂ -O-, where K ⁹ has the meanings given above.

Alkylating agents of formula (VII) are known or can be prepared by known methods.

If, in carrying out method (c) (variant γ), diisobutyl aluminum hydride is used as a reducing agent in the first stage, it is advisable to work under such conditions that are already mentioned in connection with the description of method (b, variant α) according to this invention.

If, in carrying out the method (c) (variant γ), sodium borohydride is used as a reducing agent in the first stage, then alcohols, preferably methanol, ethanol or isopropanol, are usually used as diluents.

When sodium borohydride is reduced, the reaction temperatures may vary in a certain range. Generally work at temperatures from 0 to 70 ° C, preferably from 0 to 50 ° C.

When carrying out the reduction with sodium borohydride, take an equivalent amount or an excess of sodium borohydride per 1 mole of pyrazolopyrimidine of the formula (HB). Processing is carried out in the usual ways.

When carrying out the second stage of the method (c) (variant γ) according to the invention, all the usual acid binding agents are suitable as bases. Preferably, alkali metal hydrides, alcoholates and carbonates are used, such as sodium hydride, sodium methoxide, potassium t-butoxide, sodium carbonate, potassium carbonate or lithium carbonate.

As diluents in the implementation of the second stage of the method (c) (variant γ) according to this invention, all conventional inert organic solvents are suitable. It is preferable to use ethers, such as dioxane or tetrahydrofuran, and, in addition, nitriles, such as acetonitrile.

- 11 009517

Temperatures in the implementation of the second stage of method (c) (variant γ) can vary over a wide range. Generally work at temperatures from 0 to 100 ° C, more preferably from 20 to 80 ° C.

In the implementation of the second stage of method (c) (variant γ), 1 mol of pyrazolopyrimidine of formula (1c) is generally 1-2 mol, more preferably 1-1.5 mol of alkylating agent. Processing is carried out in the usual ways.

The pyrazolopyrimidines used as starting materials in the process (6) are described in general terms by formula (I). In this formula, the radicals K ¹ , K ² , K ³ , K ⁴ and H1 are preferably of such meanings that, in connection with the description of the substances of formula (I) according to this invention, are indicated as preferred values for these radicals. To ¹⁰ preferably means hydrogen or alkyl containing 1-4 carbon atoms, more preferably means hydrogen, methyl, ethyl or propyl, each of the last three radicals being substituted by carboxyl, methoxycarbonyl or ethoxycarbonyl.

In the case of pyrazolopyrimidines of the formula (I), the substances according to the invention are meant, which can be obtained by the method (a).

According to a special variant of the method, pyrazolopyrimidines can be obtained if

K) pyrazolopyrimidine formula

N

where K ¹ , K ² , K ³ , K ⁴ , K ¹⁰ and Na1 have the meanings given above, are reacted with bromine in the presence of an inert organic diluent, such as dichloromethane, trichloromethane or carbon tetrachloride, at temperatures from -20 to + 20 ° WITH. The reaction components are preferably added in approximately equivalent amounts. Processing is carried out in the usual ways.

Alkali metal alcoholates are preferably used as strong bases in the process (6), with sodium methoxide and potassium tert-butoxide being an example.

As diluents in the implementation of method (6), all inert organic solvents that are usual for such interactions are suitable. Preferably, alcohols such as methanol or ethanol are used, as well as nitriles, such as acetonitrile.

Temperatures in the implementation of the method (6) can vary in certain intervals. Generally work at temperatures from -10 to + 80 ° C, more preferably from 0 to 60 ° C.

In carrying out the process (6), per mole of pyrazolopyrimidine of formula (16) is generally 2-3 equivalents or a higher excess of a strong base. Processing is carried out in the usual ways.

The pyrazolopyrimidines used as starting materials in the process (e) are described by the general formula (VIII). In this formula, the radicals K ¹ , K ² , K ³ , K ⁴ and H1 are preferably of such meanings that, in connection with the description of the substances of formula (I) according to this invention, are indicated as preferred values for these radicals.

Pyrazolopyrimidines of formula (VIII) are known or can be obtained by known methods (see PCT / EP 03/05 159).

The acyl derivatives used as reaction components in the process (e) are described by the general formula (IX). In this formula, the K ¹¹ radical preferably means alkyl containing 1-4 carbon atoms, more preferably methyl, ethyl or n-propyl. X ⁴ preferably means chlorine or a radical of formula

where K ¹¹ has the meanings given above.

Acyl derivatives of the formula (IX) are known or can be obtained by known methods.

As catalysts in the implementation of method (e), all reaction accelerators that are common for this type of Friedel-Crafts reactions are suitable. Metal chlorides, such as aluminum trichloride or iron (III) chloride, are preferably used.

As diluents in the implementation of method (e), all inert organic solvents that are usual for such interactions are suitable. Preferably, ethers such as diethyl ether, dioxane or tetrahydrofuran are used.

Temperatures in the implementation of method (e) can vary in a certain range. Generally work at temperatures from -20 to + 20 ° C, more preferably from -10 to + 10 ° C.

When implementing the method (e) take on 1 mole of pyrazolopyrimidine of the formula (VIII) in general 2-5

- 00 009517 moles of acyl derivative of formula (IX), as well as the corresponding amount of catalyst. Processing is carried out in the usual ways.

All solvents suitable for such halogenation reactions are suitable as diluents for the implementation of the method (ί). Preferably, halogenated aliphatic or aromatic hydrocarbons, such as chlorobenzene, are used. The halogenating agent itself, such as phosphoroxychloride or a mixture of halogenating agents, can also be used as a diluent.

Temperatures in the implementation of the method (ί) can vary over a wide range. Generally work at temperatures from 0 to 150 ° C, more preferably from 10 to 120 ° C.

In carrying out the method (ί), hydroxypyrazolopyrimidine of the general formula (X) is taken, as a rule, with an excess of halogenating agent. Processing is carried out in the usual ways.

As diluents in the implementation of method (11), all inert organic solvents that are usual for such interactions are suitable. Preferably, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol are used.

In carrying out the method (1), all inorganic and organic bases that are customary for such interactions are suitable as an acid binding agent. Preferably, tertiary amines, such as tributylamine, or pyridine are used. The amine used in excess may also be a diluent.

Temperatures in the implementation of method (1) can vary over a wide range. Generally work at temperatures from 20 to 200 ° C, more preferably from 50 to 180 ° C.

When carrying out the process (1), a heterocyclyl malonic ester of the formula (XII) and an aminopyrazole of the formula (XIII) are taken, as a rule, in equivalent amounts. However, it is also possible to use one or the other component in excess. Processing is carried out in the usual ways.

As diluents in the implementation of the methods (ί) and (|) use all common inert organic solvents. Preferably, halogenated hydrocarbons are used, such as, for example, chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles, such as acetonitrile, propionitrile, n- or isobutyronitrile, or benzonitrile; amides, such as Ν, Ν-dimethylformamide,,-dimethylacetamide, Ν-methylformanilide,-methylpyrrolidone or hexamethylphosphoric triamide; sulfoxides, such as dimethyl sulfoxide; sulfones, such as sulfolane; alcohols, such as methanol, ethanol, n- or isopropanol, n-, iso-, sec- or tertbutanol, ethanediol, propane-1,2-diol, ethoxyethanol, methoxyethanol, diethyleneglycol monomethyl ether, diethyleneglycol monoethyl ether, their mixtures with water or clean water.

As the copper salts in the implementation of the methods (ί) and (|), all the usual copper salts are suitable. Preferably, copper chloride is used) or copper bromide (C

In the implementation of the methods (ί) and (|), all common inorganic or organic bases are suitable as acceptors. Hydrides, hydroxides, amides, alcoholates, acetates, carbonates or hydrogen carbonates of alkaline earth or alkali metals are preferably used, for example, sodium hydride, sodium amide, lithium diisopropylamide, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate potassium acetate, calcium acetate, sodium carbonate, potassium carbonate, potassium bicarbonate and sodium bicarbonate, and, in addition, ammonium compounds, such as ammonium hydroxide, ammonium acetate and ammonium carbonate, as well as tertiary amines, such as trimethylamine, triethylamine, tributylamine, Ν, Ν-dimethylaniline, Ν, Ν-dimethylbenzylamine, pyridine, Νmetilpiperidin, Ν-methylmorpholine, Ν, Ν-dimethylaminopyridine, diazabicyclooctane (OABC), diazabicyclononene (ΌΒΝ) or diazabicycloundecene (ΌΒυ).

The temperatures of the reactions in the implementation of the methods (ί) and (|) can vary over a wide range. Generally work at temperatures from 0 to 150 ° C, more preferably at temperatures from 0 to 80 ° C.

When carrying out the process (ί), per mole of halopyridine of formula (XIV) is taken, as a rule, from 1 to 15 moles, more preferably from 1.3 to 8 moles of malonic ether of formula (XV). Processing is carried out in the usual ways.

When carrying out the process (|), per mole of halopyrimidine of formula (XVI) is taken, as a rule, from 1 to 15 moles, more preferably from 1.3 to 8 moles of malonic ester of formula (XV). Processing is carried out in the usual ways.

All the above methods are carried out mainly at atmospheric pressure. However, it is also possible to work at elevated pressure.

The compounds exhibit a strong microbicidal effect and can be used to combat unwanted microorganisms, such as fungi and bacteria, when protecting plants and protecting materials.

Fungicides are used in plant protection to combat P1-8 inburyogousse8, Ootues1c8. С1у1пбютуес1с8. Auditorium, A8cotussee1, WA81butussee18 and Hainanus8.

Bactericides are used in plant protection to combat rzeibotbabaseaee, YOU / Oeaseee, En

- 13 009517

One of yours. Warriors and terrestrial dogs.

As an example. but not limited to this. You can call some pathogens of fungal and bacterial diseases. which fall under the generic terms listed above:

species of the genus xantomonas (hayotok). such as. eg. Hayotopak SatrekPzk ru.ogu / AE; species of the genus Pseudomonas (Rkeikotopak). such as. eg. Rkeikotopak kupdaye ru.1asygutapk; species of the genus Ervinia (Έπνίπίη). such as. eg. Er \\\ 'ypa atuoyota;

Pytium species (Ru1Yit). such as. eg. Rukshin and Shtit;

species of the phytophtora (Ryu1ori1yota). such as. eg. Ryuori1yota shGek1apk;

Species of the genus Pseudoperonospore (Rkeikoretopokrot). such as. eg. Riekoreporecota Yiti or Rkeioretopokrota sybekkk;

species of the plasmopar genus (P1actorga). such as. eg. Pactus uSch1a;

species of the genus Bremia (Vget1a). such as. eg. Vget1a 1asisae;

species of the genus peronospore (Regoprocrog). such as. eg. Regokokrog ry or R. lakkkkay;

species of the genus Erizif (Etuyrye). such as. eg. Etuyrye dgatiyk;

Species of the genus of the sphere library (8yayo1yesa). such as. eg. 8ryayo! Iesa Giidshea;

species of the subsosphere (Rokokrjeega). such as. eg. Rokokryaega 1Eisoitsya;

species of the genus Venturia (Ueshshta). such as. eg. Ueshshta shaadiik;

species of the pyrenophore (Rugeporyoga). such as. eg. Rugeporyyoga 1tek or R. dattshea (conidia form: Drexler. Syn: gelmintosporium);

Species of the genus Kokhliobolyus (Sosylyukoik). such as. eg. Sosylobali kaszpk (conidia form: Drexler. Syn: gelmintosporium);

species of the genus Uromicez (Ittosek). such as. eg. Itotusek arrepk1s1a1ik;

Species of the genus Puccinia (Riesssha). such as. eg. RissShsha Tesopkya;

species of the genus sclerotinia (8c1eto11sh). such as. eg. 8s1gx xx1gogogogit;

species of the genus tilletia (TSheya). such as. eg. TSheya Sapek;

species of the genus ustilago (IkShado). such as. eg. IkShado Peak or IkShado Auepae;

Species of the genus Pellicularia (Reschapa). such as. eg. REHSSHAPA KAKAKP;

Species of the genus Pyrikularia (Rupschapa). such as. eg. RupsShapa okhuhe;

species of the genus Fusarium (Bikatsht). such as. eg. Bikatsh. c1shotish;

Species of the Botrytis genus (VoyuNk). such as. eg. Voyuik shchetea;

Species of the genus Septoria (Simonopus). such as. eg. Pondite pokerite;

species of the leptospheric genus (phytosteria 1a). such as. eg. Leptocorya 1a pokogite;

species of the genus of churches (Segokrog). such as. eg. Segokroga sapheksepk;

Species of the genus Alternaria (Lietpapa). such as. eg. Liegpapa Lacagca;

Species of the genus Pseudosporella (Rkeikosesetrokroteya). such as. eg. Rikikosetsokroteya ergosyokkek.

The biologically active substances according to this invention also show a strongly strengthening effect on plants. Therefore, they are suitable for activating the plant’s own defenses against an attack of unwanted microorganisms.

Under the substances. strengthening plants (inducing resistance). should be understood in this context such substances. which can thus stimulate the plant defense system. that the treated plants in subsequent inoculation with undesirable microorganisms exhibit long-term resistance to these microorganisms.

Under undesirable microorganisms in this case should be understood phytopathogenic fungi. bacteria and viruses. The substances according to the invention can thus be used in order. to protect the plants for a certain period of time after treatment from the attack of these harmful pathogens. Time interval. during which protection is developed. is generally from 1 to 10 days. preferably from 1 to 7 days after treatment of plants with biologically active substances.

Good tolerance by plants of these biologically active substances in concentrations. necessary to combat plant diseases. allows processing of plant parts. located above the soil surface. treatment of planting and seed material and soil.

In this case, the biologically active substances according to the invention can be used with particularly good success for the control of diseases of cereals. eg. against Etuyrie-species and with diseases in viticulture. horticulture and vegetable production. eg. against the Voyuik-. UipShpa8ryayo1yes- and Rokokryaega-species.

The biologically active substances according to the invention are also suitable for increasing the yield. Besides. they have low toxicity and are well tolerated by plants.

Biologically active substances according to this invention can, if necessary, in certain concentrations and consumable amounts be used as herbicides to affect plant growth. and also to combat animal pests. They can be used. when necessary

- 14 009517 STI, as intermediate and initial products for the synthesis of other biologically active substances.

According to the invention, all plants and parts of plants can be treated. Here, plants are understood as all plants and plant populations, such as desirable and undesirable wild plants or cultivated plants (including naturally occurring cultivated plants). Cultivated plants also include plants that can be obtained by conventional breeding or optimizing methods, or biotechnological and genetic technology methods, or a combination of these methods, including transgenic plants and including plant varieties, protected or not protected by the rights of protection of the variety. Plant parts are all overground and underground parts and plant organs, such as sprouts, leaves, inflorescences and roots, with leaves, needles, stems, stems, inflorescences, fruits, fruits and seeds, as well as roots, tubers and rhizomes. Parts of plants include crops, as well as vegetative and generative propagation material, such as seedlings, tubers, rhizomes, cuttings and seeds.

The treatment of plants and plant parts according to the present invention with biologically active substances is carried out directly or by impact on the environment, habitat and storage room by conventional treatment methods, for example, dipping, spraying, steam generation, mist formation, spraying, smearing, injection, and breeding material, in particular, seeds also monolayer or multilayer coating.

In the case of the protection of materials, the substances according to the invention are used to protect technical materials from attack and destruction by unwanted microorganisms.

In this context, technical materials are understood as non-living materials that are prepared for use in engineering. For example, technical materials that can be protected by biologically active substances according to this invention from changes and destruction caused by microbes include adhesives, clays, paper and cardboard, textiles, leather, wood, dyes and plastic products, cooling lubricants and other materials that may be attacked or destroyed by microorganisms. The materials to be protected also include parts of industrial installations, for example, cooling water circulation pipelines, which may be affected by the multiplication of microorganisms. In the framework of this invention, adhesives, clays, paper and cardboard, leather, wood, coloring agents, cooling lubricants and heat transfer fluids, particularly preferably wood, should preferably be mentioned as technical materials.

As microorganisms that can cause destruction or alteration of technical materials, for example, bacteria, fungi, yeast, algae, and slug organisms can be called. The biologically active substances according to the invention preferably act on fungi, in particular on mold fungi, on fungi that stain wood and destroy wood (Vayabyushus), as well as on slug mushrooms and on algae.

As an example may be mentioned are microorganisms of the following genera: Alternaria (LNegpapa), species such as LNegpapa 1epsh8, Aspergillus (LkregdShik), species such as LkregdShik looking hetomium (Syae otsht!), Species such as SNaeYutsht d1oo8it, koniofora (Soshoryoga), these types of how Soshoryoga Rie! Aia, lentinus (Bep11ii8), species such as BepNpih bdgshik, Penicillium (Penicillium), species such as Penicillium d1aisit, polyporus (Ro1urogi§), species such as Ro1urogi8 ueg§1so1og, aureobazidium (Ligeoayabsht), species such as More often, the scleroma (scleroma), such as 8 й ор,,,,,, виды виды 8 8 8 8 8 8 8 8 8 8 8 8 8

Biologically active substances, depending on their inherent physical and / or chemical properties, can be converted into conventional formulations, such as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, into very small capsules in polymeric substances and into coating masses. for seed material, as well as in the finished form with ultra-small volume for the formation of cold and hot mist.

These formulations are prepared in a known manner, for example, by mixing the active substances with fillers, that is, with solvents, with liquefied gases under pressure, and / or with solid carriers, optionally using surfactants, that is, emulsifying agents and / or dispersing agents, and / or blowing agents. If water is used as a diluent, for example, organic solvents can also be used as auxiliary solvents. As liquid solvents, essentially aromatic compounds such as xylene, toluene or alkyl naphthalenes, chlorinated aromatic or chlorinated aliphatic hydrocarbons, such as chlorobenzenes, chloroethylenes or methylene chloride, aliphatic hydrocarbons, such as cyclohexane or paraffins, for example, alcohols, such as butanol or glycol, as well as their esters and esters, ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, highly polar solvents, e as dimethylformamide and dimethyl sulfoxide, as well as water. Under liquefied

- 15 009517 gaseous diluents or carriers understand such liquids that are gaseous at normal temperature and normal pressure, for example aerosol foaming gases such as halohydrocarbons, as well as butane, propane, nitrogen and carbon dioxide. As solid carriers, for example, grinding of natural rocks, such as kaolin, alumina, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth, and grinding of synthetic stones, such as highly dispersed silicic acid, alumina and silicates, are meant. As solid carriers for granules, crushed and fractionated natural stone rocks, such as calcite, marble, pumice, sepiolite, dolomite, as well as synthetic granules from inorganic and organic flour, as well as granulates from organic material, such as sawdust, are meant coconut shells, corn stalks and tobacco stalks. As emulsifying and / or foaming agents, for example, nonionic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohols, for example alkyl aryl polyglycol ether, alkyl sulfonates, alkyl sulfates, arylsulfonates, and egg white hydrolysates, are also meant. As dispersing agents, for example, lignin sulfite liquors and methylcellulose are meant.

Adhesive agents such as carboxymethylcellulose, natural and synthetic powdered, granular or latex form polymers such as gum arabic, polyvinyl alcohol, polyvinyl acetate, and also natural phospholipids, such as kefalins and lecithins, and synthetic phospholipids, can be used in finished form preparations. Other additives can be mineral and vegetable oils.

Dyes such as inorganic pigments such as iron oxide, titanium oxide, ferrocyan blue and organic dyes such as alizarin, azo and metal phthalocyanine dyes and trace amounts of nutrients such as iron, manganese, boron, copper, cobalt, molybdenum and zinc.

The finished formulations of preparations contain, as a rule, from 0.1 to 95% by weight of biologically active substance, preferably from 0.5 to 90% by weight.

Biologically active substances according to the present invention can be used alone or in their ready-made formulations and in mixture with known fungicides, bactericides, acaricides, nematicides or insecticides, for example, in order to broaden the spectrum of action or to prevent the development of resistance to them. In many cases, this creates synergistic effects, that is, the efficiency of the mixture is higher than the sum of the efficiencies of the components in a separate application.

As an admixed component, for example, the following compounds can be used. Fungicides

2-phenylphenol; 8-hydroxyquinoline sulfate; acibenzene-8-methyl; aldimorph; amidoflumet; ampropylphos; ampropylphosphate; andoprim; anilazines; aaconazoles; azoxystrobin; benalaxyl; benodanil; benomyl; benthiavalicarbizopropyl; benzamacryl / benzamacryl-isobutyl; bilanaphos; binalacryl; biphenyl; betertanol; Blasticidin-8; bromuconazole; bupirimaty; butiobates; butylamine; calcium polysulfide; capsimycin; captafol; captan; carbendazim; carboxin; carpropamide; carvones; quinomethionate; chlobenthiazones; chlorphenazoles; Chloroneb; chlorothalonil; hlozolinaty; closilacon; cyazofamide; cyflufenamide; cymoxanil; cyproconazoles; cyprodinil; ciprofuram; Dagger 6; debacarb; dichlofluanid; dichlones; dichlorophene; diclocyme; diclomesins; dicloran; diethofencarb; difenoconazoles; diflumetorim; dimethyromol; dimethomorph; dimoxystrobin; diniconazoles; diniconazoles-M; dinocap; diphenylamines; dipyritions; ditalimfos; dithianon; dodin; Drazoxolone; Edifenphos; epoxiconazoles; ethaboxam; ethyrimol; etridiazoles; famoxadone; fenamidones; phenapanil; fenarimol; benbuconazole; fenfuram; fenhexamide; fenitropane; phenoxanil; fenpiclonil; fenpropidin; fenpropimorph; ferbam; fluazinam; flubenzimine; fludioxonil; flumetover; flumorph; fluoromidy; fluoxastrobin; fluquinconazole; flurprimidol; flusilazoles; flusulfonamides; flutolanil; flutriafol; folpet; fosetyl-A1; fosetyl sodium; fuberidazoles; furalaxyl; furametpyr; furcarbanil; furmecyclox; guazatiny; hexachlorobenzenes; hexaconazole; hymexazole; imazalil; imbenconazoles; iminoctadine triacetates; iminoctadine tris (albesil); iodocarb; ipconazole; iprobenfos; iprodiones; iprovalicarb; irumamycin; isoprothiolans; isovalentones; Kasugamycin; kresoximmethyl; mancozeb; maneb; meferimzones; mepanipyrim; mepronil; metalaxyl; metalaxyl-M; metconazoles; metasulfocarb; metforoxam; metiram; metominostrobin; metsulfovaks; Mildiomycin; miklobutanil; myclozolin; natamycin; nicobifen; nitrotalisopropyl; Noviflumuron; nuarimol; Ofuratsy; orizastrobin; oxadixyl; oxolinic acid; oxpoconazoles; hydroxycarboxine; oxyfentiine; paclobutrazole; pefurazoates; penconazoles; penzicuron; fosdiphen; phthalides; picoxystrobin; piperalin; polyoxins; polyoxorim; probenazoles; prochloraz; procymidones; propamocarb; propanosine sodium; propiconazole; propineb; proquinazid; prothioconazoles; pyraclostrobin; pyrazophos; pyrifenox; pyrimethanil; pyroquilone; Piroxyfur; pyrroliteny; quinconazoles; quinoxyfen; Quintosenes; symeconazole; spiroxamines; sulfur; tebuconazole; tecophthalm; technazenes; tetcyclacis; tetraconazoles; thiabendazole; titsiofen; tyfluzamida; thiophanatemethyl; thiram; thioximide; tolclofosmetil; tolylfluanid; triadimefon; tri- 16 009517 dimenol; triazbutyl; triazoxides; tricyclamides; tricyclazole; tridemorph; trifloxystrobin; triflumisoles; triforina; triticonazoles; uniconazoles; validamycin A; vinclozolin; zineb; ziram; zoxamides; (28) -I- [2- [4 - [[3- (4-chlorophenyl) -2-propynyl] oxy] -3-methoxyphenyl] ethyl] -3-methyl-2 [(methylsulfonyl) amino] butanamide; 1 - (1-naphthalenyl) -1H-pyrrole-2,5-dione; 2,3,5,6-tetrachloro-4 (methylsulfonyl) pyridine; 2-amino-4-methyl-L-phenyl-5-thiazolecarboxamide; 2-chloro-y- (2,3-dihydro1,1,3-trimethyl-1H-inden-4-yl) -3-pyridine carboxamide; 3,4,5-trichloro-2,6-pyridinedicarbonitrile; actinovates; cis-1- (4-chlorophenyl) -2- (1H-1,2,4-triazol-1-yl) -cycloheptanol; methyl 1- (2,3-dihydro-2,2-dimethyl-1H-inden-1-yl) -1H-imidazol-5-carboxylate; potassium bicarbonate; L- (6-methoxy-3-pyridinyl) cyclopropanecarboxamyl; sodium tetrathiocarbonate; as well as copper salts and copper preparations, such as the Bordeaux mixture; copper hydroxide; copper naphthenate; copper oxychloride; copper sulfate; kufraneb; copper oxide; mancopper; oxinecopper.

Bactericides

Bronopol, dichlorophene, nitrapirin, nickel dimethyldithiocarbamate, kasugamycin, octylinone, furancarboxylic acid, oxytetracycline, probenazole, streptomycin, tecloflam, copper sulfate and other copper preparations.

Insecticides / Acaricides / Nematicides

Abamectin, ABS-9008, acephate, atsekvinotsil, acetamiprid, acetoprole, acrinathrin, ΑΚΌ-1022, ΑΚΌ-3059, ΑΚΌ-3088, alanycarb, aldicarb, aldoksikarb, allethrin, allethrin 1st isomers alphacipermetrin (alphamethrin), amidoflumet, aminokarb, amitraz, avermectin, az, 60541, azadirachtin, azamethiphos, azinphos-methyl, azinfosetil, azocyclotin, VasShik rorBBae, VasShik krBaepsik, VasShik kiΙίΙίδ, VasShik 1Big1pd1epk1k, VasShik 1kig1pd1epk1k line EU-2348, VasShik 1ig1pts1epk1k line SS-91, VasB1ik 1ig1pts1epk1k line YSTS-11821 , baculoviruses, Veaiuepa Lakyapa, Veaiuepa 1epe11a, bendiocarb, benfu acaron bens VTS-504, VTS-505, buts hl orfenovos, chlorofibers coumaphos, cyanofenphos, cyanophos, cyclopenes, cycloprotin, Subrotomela, cyfluthrin, cygalothrin, cyhexatin, cypermethrin, cyphenothrin (1 I-trans-isomer), cyromazines, ΌΌΤ, deltamethrin, demeton-8-methyl, demeton-metomectane, cyromazines, ΌΌΤ, deltamethrin, demeton-8-methyl, demeton-metomectane, cyromasins, , diazinon, dichlofenthion, dichl Orvos, Dicorolt crc, esfenvalerati fe sulforanillo furfenprox (fluproxifen), furatiocarb, gamma, gossipryra ndokarb MeShagyhshit, mehkarbesh, mexaphazones, mehocrybrose, mexacryb, mexaphaze, mexaphaze, mexaphaze, mexaphaze, mexaphazi , N ^ 170, N ^ 184, N ^ 194, N ^ 196, niclosamides, nicotines , nitenpyram, nitiazines, ΝΝΕ0001, ΝΝΕ0101,-0250, ΝΝΕ9768, Novaluron, Noviflumuron, 0Κ 5101, 0-5201, 0Κ-9601, 0Κ-9602, 0Κ9701, 0Κ-9802, ometoate, oxamyl, oxime, octoprotein, 0ес-9601, 0-9602, 0Κ9701, 0Κ-9802, ometoate, oxamyl, oxymethyne, 3, 0Κ9701, 0Κ-9802, ometoate, oxamyl, oxime, octoprotein, 0ес-9601, 0-9602, 0Κ9701, 0Κ-9802, ometoate, oxamyl, oxymethyne, 3, 0-9012, 0 9-9012, omethate, oxamyl, oxymethyme, oxymethyl, omethyl, oxymethyl, omethate parathionmethyl, parathion (-ethyl), permethrin (cis-, trans-), petroleum, PH-6045, fenotrin (1I-trans-isomer), fentoates, forates, fosalon, phosmet, phosphamidone, phosphocarb, phoxim, piperonyl butoxides, pyrimocarb , pyrimiphosmethyl, pyrimiphosethyl, pleralthrin, profenofos, promekarb, propaphos, propargites, propetamphos, propoxur, prothiophos, prototes, protrifenbutes, pymetrosines, pyraclofos, feast smetrin, feverfew, pyridaben, pyridalyl, pyridaphenthion, piridation, Pyrimidifen, pyriproxyfen, kvinalfos, resmethrin, JAN-5849, ribavirin, Yai-12457, Yai-15525, 8-421, 8-1833, salition, sebufos, 8E0009, silafluofen, spinosad, spirodiclofen, spiromesifen, sulfluramide, sulfotep, sulprofos, taufluvalinaty, tebufenozida, tebufenpyrad, tebupirimfos, teflubenzuron, teflutrin, temefos, those

- 17 009517 vinfu , tralotsitrin, tralomethrin, transfluthrin, triarateny, triazamate, triazophos, triazuron, trihlofenidiny, trichlorfon, triflumuron, trimetakarb, vamidothion, vaniliprole, verbutin, UegbsShsht 1esail, e L-108,477, ^ Z-40027, ΥΙ5201, ΥΙ-5301, ΥΙ- 5302, CMS, xylilcarb, ΖΑ-3274, zeta-cypermethrin, zolaprof OS, ΖΧΙ-8901, compound 3-methylphenylpropylcarbamate (tsumacide Ζ), compound 3- (5-chloro-3-pyridinyl) -8- (2,2,2 trifluoroethyl) -8-azabicyclo [3.2.1] octane-3- carbonitrile (СА8-Кед.-№. 185982-80-3) and the corresponding 3-endo-isomers (СА8-Кед.-№. 185984-60-5) (see νθ 96/37494, νθ 98/25923), as well as preparations that contain insecticidal plant extracts, nematodes, fungi or viruses.

It is also possible to mix with other known biologically active substances, such as herbicides, or with fertilizers and plant growth regulators, protective substances, respectively, semi-chemicals.

In addition, the compounds of formula (I) according to this invention exhibit a very good antimycotic (antifungal) effect. They have a very broad antimycotic spectrum of action, especially in relation to dermatophytes and process fungi, mold and diffuse fungi (for example, in relation to Saibl-like species, such as Sahb1b a1Hsai8, Saib1b d1aBga1a), as well as Er1begtory1 and Psorit. AkregdShik-vidam, such as AkregdShik shdeg and AkregdShik GshshdTsch. Tpsyoryyi-species such as Tpsyoryyyuyiadigoryuye8, Mkgokroyi-sidami, such as Mkgokroogoi sai18 and aviboshii. The enumeration of these fungi in no way limits the covered mycotic spectrum, but is only illustrative.

In addition, the compounds of formula (I) according to the invention are suitable for suppressing the growth of tumor cells in humans and mammals. This property is based on the interaction of the compounds according to this invention with tubules and microtubules and facilitating the polymerization of microtubules.

For this purpose, an effective amount of one or more compounds of the formula (Ι) or their pharmaceutically acceptable salts thereof should be taken.

Biologically active substances can be used by themselves, in the form of ready-made forms of their preparations or in the form of prepared from them forms ready for use, such as ready-for-use solutions, suspensions, powders for spraying, pastes, soluble powders, spraying agents and granulates. . The application is carried out in the usual ways, for example, by watering, spraying, spraying, spraying, spraying, foaming, lubrication, etc. Next, you can apply biologically active substances in the way of ultra-small volumes or inject the preparation of the active substance or the active substance itself into the soil. You can also process the seed of plants.

When using the biologically active substances of the present invention as fungicides, the amounts used can vary over a wide range depending on the method of application. When processing parts of plants, the applied amounts of biologically active substances are, as a rule, from 0.1 to 10,000 g / ha, preferably from 10 to 1000 g / ha. When treating seed, the amounts of biologically active substance used are, as a rule, from 0.001 to 50 g per kilogram of seed, preferably from 0.01 to 10 g per kilogram of seed. When tillage, the applied amount of biologically active substances are, as a rule, from 0.1 to 10,000 g / ha, preferably from 1 to 5,000 g / ha.

As already mentioned above, it is possible according to the invention to process all plants and their parts. In one of the preferred embodiments, plants that are encountered in the wild or are obtained by conventional biological selection methods, such as crossing, protoplasm fusion: plant species and plant varieties, as well as parts thereof. In another preferred embodiment of this invention, transgenic plants and plant varieties are processed, which are obtained by genetic engineering methods, if necessary, in combination with conventional methods (genetically modified organisms) and plant parts. The concept of a part, respectively, of a part of a plant is explained above.

Particularly preferably, in accordance with the present invention, plants which are usually marketed or used plant varieties are treated. Plant varieties are understood to be plants with new properties (treits), which are bred by ordinary selection, using mutagenesis or using recombinant DNA technology. These can be varieties, races, bio and genotypes.

Depending on plant species, respectively, plant varieties, their location and growth conditions (soil, climate, vegetation period, nutrition), superadditive (synergistic) effects can be observed during the treatment according to this invention. For example, it is possible to reduce the applied amount and / or expansion of the spectrum of action, and / or enhance the effect of the substances and agents used according to the invention, improved plant growth, increased tolerance towards high or low temperatures, increased tolerance to dryness or with respect to salt content in water or soil, increased flowering efficiency, easier collection

- 18 009517 harvest, accelerated ripening, increased yields, higher quality and / or high nutritional value of crop products, better shelf life and / or better processability of crop products that go beyond the expected effects.

Preferred transgenic (obtained using gene technologies) plants, respectively, plant varieties that can be processed according to this invention, include all plants that received genetic material as a result of a genetic modification that gave these plants particular preferred properties (treits). Examples of such properties are better plant growth, increased tolerance to high or low temperatures, increased tolerance to dryness or to the salt content of water or soil, increased flowering efficiency, easier harvesting, faster ripening, higher yields, higher the quality and / or high nutritional value of the products of the crop, the best persistence and / or the best processability of the products of the crop. Other and particularly preferred examples of such properties are increased plant protection against animals and microbial pests, such as insects, ticks, fungi pathogenic for plants, bacteria and / or viruses, as well as increased plant tolerance towards certain herbicidally active substances. As an example of transgenic plants, important cultivated plants should be mentioned, such as grain crops (wheat, rice), corn, soybeans, potatoes, cotton, tobacco, canola, and fruit plants (with fruits such as apples, pears, citrus fruits and grapes), with corn, soybeans, potatoes, cotton, tobacco, and rapeseed being particularly preferred. As properties (treits), increased plant protection with respect to insects, arachnid animals, nematodes and snails, caused by toxins in plants, especially those created in plants with the help of Vaschik ShippTepik genetic material (for example, using genes Thu1A (a), Thu1A (b), Thu1A (s), Thu11A, Thu111A, Thu111V2, Thu9s Thu2AH, Thu3Vb and Sgu1R, and their combinations) (hereinafter B1 plants). As properties (treits), enhanced plant protection against fungi, bacteria and viruses with system-acquired resistance (resistance) (SVR), systemine, phytoalexin, elititor, as well as resistant genes and appropriately expressed proteins and toxins are also particularly preferred. As properties (treits), an increased tolerance of plants to certain herbicidally active substances, for example imidazolinones, sulfonylureas, glyphosates or phosphinothricin (for example, PAT gene), is particularly preferred. Genes that impart desirable properties (treits) in each case can occur in transgenic plants and in combinations with each other. As an example of B1 plants, there are maize varieties, cotton varieties, soybean varieties, and potato varieties that are marketed under the trademarks SAEAE (for example, corn, cotton, soybean), KposOSH® (for example, maize), and Garmin® (for example, corn), WoDdagb® (cotton), ShsoUp® (cotton) and No. \\ EhaG® (potato). Examples of herbicide-tolerant plants include maize varieties, cotton varieties, and soybean varieties that are marketed under the trademarks Yaoipbir Yaeebu® (glyphosate tolerance, for example, maize, cotton, soybean), Liouw Ipk® (tolerance to phosphinotry). for example, rapeseed), ΙΜΙ® (tolerance to imidazolinones) and ZTZ®® (tolerance to sulfonylureas, for example, corn). As herbicide-resistant (especially for herbicide tolerance of the bred) plants, varieties supplied under the trademark C1eagie1b® (for example, corn) should also be mentioned. It goes without saying that these statements are also valid for plant varieties that will be created in the future, respectively, will be offered on the market with these properties or with newly created genetic properties (treits).

These plants can be particularly preferably treated according to the invention with compounds of the general formula (Ι), respectively, with mixtures of biologically active substances according to the invention. The preferred areas given above for biologically active substances, respectively, mixtures, are also suitable for treating these plants. Particularly preferable is the treatment of plants with the compounds specifically given earlier in the text, respectively mixtures.

The preparation and use of biologically active substances according to this invention can be seen from the examples below.

Examples of obtaining compounds of example 1

(Method a)

To a solution of 0.2 g (0.56 mmol) 3-cyano-5,7-dichloro-6- (3-trifluoromethylpyridin-2-yl) pyrazolo [1,5-a] pyrimidine in 10 ml of acetonitrile add 0.065 g ( 1.12 mmol) of potassium fluoride, stirred in flow

- 19009517 NII 2 h at a temperature of 80 ° C and finally cooled to 0 ° C. 0.13 g (1.17 mmol) (8) -2,2,2-trifluoro-isopropylamine is added to this solution and stirred for 18 hours at a temperature of 80 ° C. After that, the reaction mixture is cooled to room temperature and 30 ml of diluted hydrochloric acid are mixed. Extracted with dichloromethane, the organic phase is washed twice with water, dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue is mixed with a mixture of petroleum ether / methyl tert-butyl ether = 15: 1 and filtered through a short silica gel column. Thus, 0.15 g (58.5% of theor.) 3-cyano-5-chloro-6- (3-trifluoromethylpyridin-2-yl) pyrazolo [1,5-a] -pyrimidine-Y - [(( 1,8) -2,2,2-trifluoro-1-methylethyl] amine.

HPLC (high pressure liquid chromatography): 1ODP = 3.14.

The above methods also provide the pyrazolopyrimidines of the formula given in Table 1

- 20 009517

- 21 009517

- 22 009517

Obtaining initial products of the formula (II) example 65

ΟΝ

Method (ί)

To a mixture consisting of 5.8 g (18.1 mmol) of 3-cyano-6- (3-trifluoromethylpyridin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol and 22.15 g (144.5 mmol) of phosphorus oxychloride, add at room temperature with stirring 3.0 g (14.5 mmol) of phosphorus pentachloride in five portions. The reaction mixture is heated for 4 hours with reflux, then cooled to room temperature and the solvent is distilled off under reduced pressure. To the obtained residue add 100 ml of water and then

- 23 009517 extracted three times with 100 ml of dichloromethane. The combined organic phases are washed twice with 50 ml of water, dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue obtained is chromatographed using hexane / ethyl acetate = 3: 1 on silica gel. Obtain 0.88 g (14.8% of Theor.) 3-cyano-5,7-dichloro-6- (3-trifluoromethylpyridin-2-yl) -pyrazolo [1,5-a] pyrimidine.

HPLC: 1 ° P = 2.68.

Example 66

ΟΝ

To a mixture consisting of 2.0 g (10.74 mmol) of 2-thienylmalonic acid and 1.16 g (10.74 mmol) of 3-amino-4-cyanopyrazole was added at room temperature with stirring for 2 minutes 41.13 g ( 268 mmol) of phosphorus oxychloride. After that, heated for 18 hours at a temperature of 90 ° C and then cooled to room temperature. 250 ml of ice-cold water are added to the reaction mixture and the suspension obtained is stirred for 1 hour. The mixture is filtered with suction and washed with 50 ml of water. For further purification, the product is suspended in 50 ml of cyclohexane / ethyl acetate = 1: 1 and boiled for a short time, then cooled, sucked off through a short silica gel column and washed 8 times with 50 ml of cyclohexane / ethyl acetate = 1: 1. The filtrate is dried over sodium sulfate and then re-filtered. The residue after filtration is washed with malt the amount of cyclohexane / ethyl acetate = 1: 1. From the combined filtrate, the solvent is distilled off under reduced pressure. Obtain 1.48 g (30,34% of Theor.) 5,7 dichloro-3-cyano-6- (thien-3-yl) pyrazolo [1,5-a] pyrimidine as a solid.

Example 67

Through a solution of 7.5 g (25.41 mmol) of 5,7-dichloro-3-cyano-6- (thien-3-yl) pyrazolo [1,5-a] pyrimidine in 80 ml of dichloromethane is passed at temperatures from -5 ° C to 0 ° C for two hours a tray of chlorine gas. After that, the reaction mixture is heated to room temperature and the solvent is distilled off under reduced pressure. Dichloromethane is added to the residue obtained and it is filtered off with suction. You get 2.0 g of the desired product. The previously collected filtrate, after distilling off the solvent, is chromatographed with cyclohexane / ethyl acetate = 1: 1 on silica gel. After distilling off the solvent, another 3.5 g of the desired product is isolated from the eluate. In this way, only 5.5 g (54.13% of theor.) Of 5,7-dichloro-3-cyano- (2,5-dichloro-thien-3-yl) pyrazolo [1,5-a] pyrimidine is obtained.

Getting the original product of the formula (X).

Example 68

Method (11)

A mixture consisting of 4.1 g (14.8 mol) of dimethyl ester of 2- (3-trifluoromethylpyridin-2-yl) malonic acid, 1.6 g (14.8 mmol) of 3-amino-4-cyanopyrazole and 3, 02 g (16.3 mmol) of tri-n-butylamine are stirred for 2 hours while heating at 180 ° C. At the same time, the methanol formed during the reaction is constantly distilled off. Finally, the reaction mixture is cooled to room temperature. The separated tri-n-butylamine is decanted and the remaining mixture is distilled under reduced pressure. Obtain 5.8 g of the product which, according to the HPLC, 60% consists of 3-cyano-6- (3-trifluoromethylpyridin-2-yl) pyrazolo [1,5-a] -pyrimidine-5,7-diol. The yield calculated from here is 73.25% of the theory. The product is used without further purification for further synthesis.

HPLC: 1 ° P = 0.29.

Obtaining the original product of the formula (CP-a)

Example 69

Method (1)

I ch ₃

- 24 009517 g (207 mmol) 60% suspension of sodium hydride suspended in 300 ml of dioxane. 27.29 g (206.6 mmol) of malonic acid dimethyl ester are added dropwise at a temperature of 55-60 ° C to it and continue stirring for 30 minutes at the same temperature. After the addition of 8.18 g (82.63 mmol) of copper (1) chloride, the mixture is heated to 80 ° C and 15 g (82.63 mmol) of 2-chloro-3 trifluoromethylpiperidine are added dropwise. The reaction mixture is stirred for another 14 hours at 100 ° C. After the final cooling to a temperature of 15-20 ° C, concentrated hydrochloric acid is slowly added dropwise until the mixture gives an acidic reaction. Now add 600 ml of water and 300 ml of dichloromethane and filter off insoluble components. The organic phase is separated from the filtrate, dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue is chromatographed with hexane / acetic acid ester (4: 1) on silica gel. 10.1 g (40% of theor.) 2 - [(3-trifluoromethyl) pyrimidin-2-yl] malonic acid dimethyl ester are obtained.

HPLC: 1 ° P = 2.05.

Getting the original product of the formula (X11-b).

Example 70

Method (])

2.6 g (65.4 mmol) of a 60% sodium hydride suspension are suspended in 100 ml of tetrahydrofuran. To the suspension at a temperature of about 0 ° C, 6.9 g (52.4 mmlsl) of malonic acid dimethyl ester are added and stirred for 0.5 hours at the same temperature. Finally, a solution of 6.5 g (43.63 mmol) of 4,5-dichloropyrimidine in 50 ml of tetrahydrofuran is added dropwise and the mixture is stirred for 3 hours at room temperature. After this, 150 ml of 1N hydrochloric acid are slowly added dropwise and then extracted with 100 ml of dichloromethane. The organic phase is separated, dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue is chromatographed with methyl t-butyl ether / petroleum ether (1: 9) on silica gel. 7 g (65.6% of the theory) of 2- (5-chloropyrimidin-4-yl) -malonic acid dimethyl ester are obtained.

HPLC: 1 ° P = 1.33.

Example 71 Preparation of 4,5-Dichloropyrimidine

To a solution of 112.5 g (673.7 mmol) of 5-chloro-6-oxo-1,6-dihydropyrimidin-1-ih chloride in 630 ml of phosphoroxychloride add 1.6 ml of dimethylamine and heat for 3 hours during reverse distillation. After that, excess phosphorus oxychloride is distilled off under reduced pressure. After cooling, the residue is poured into 1.5 l of ice-cold water, extracted with 500 ml of dichloromethane, the organic phase is dried over sodium sulfate and the solvent is distilled off under reduced pressure. 72.3 g (66.3% of the theory) of 4,4-dichloropyrimidine are obtained. HPLC: 1OD = 1.35.

Example 72. Preparation of 5-chloro-6-oxo-1,6-dihydropyrimidin-1-i chloride

To a solution of 77 g (0.8 mol) of 4 (3H) -pyrimidinone in 770 ml of ice-vinegar add 6.5 g (40 mmol) of ferric chloride (III) and serve in a solution for 2 hours at a temperature of 40-45 ° С 113.6 g (1.6 mol) of chlorine. The reaction mixture is cooled to 15 ° C, the resulting solid product is sucked off and washed with ether. 112.5 g (84% of theor.) Of 5-chloro-6-oxo-1,6-dihydropyrimidin-1-ih chloride are obtained.

Example 73 Preparation of 4 (3H) -pyrimidinone

A mixture of 103 g (0.804 mol) of 6-mercapto-4 (1H) -pyrimidinone (DR 50053381, SN.Ayg. ΟΆΝ 84: 17404) and 141.5 g (1.2 mol) of Raney nickel in 1.2 l of ethanol in for 8 h, heated by reverse distillation. The solution is filtered while hot, the residue is washed with ethanol and the solvent is distilled off from the filtrate under reduced pressure. 67.2 g (87% of theor.) 4 (3H) -pyrimidinone are obtained.

*) Determination of 1ODP values is carried out according to the EES-EpesDue 79/831 Apech V. A8 instructions using the HPLC (gradient method, acetonitrile / 0.1% aqueous phosphoric acid).

- 25 009517

Example 74

A mixture consisting of 5 mmol of 5,7-dichloro-6- (5-chloropyrimidin-4-yl) -3-formylpyrazolo [1,5-a] pyrimidine, 5 mmol of 4-methylpiperidine and 5 mmol of potassium carbonate in 30 ml of acetonitrile Stir for 15 hours at room temperature. After that, the reaction mixture is placed in 120 ml of water. Three times extracted with ethyl acetate, the combined organic phases are dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue obtained is chromatographed with cyclohexane / ethyl acetate = 3: 1 on silica gel. Thus, 1.15 mmol of 5-chloro-6- (5-chloropyrimidin-4-yl) -3-formyl-7- (4-methylpiperidin-1-yl) pyrazolo [1,5-a] pyrimidine is obtained.

HPLC: 1 g P = 3.04.

Example 75

sn ~ sn ₂

In a solution of 1.4 mmol of methyltriphenyl phosphonium bromide and 1.4 mmol of n-butyl lithium in 58 ml of tetrahydrofuran are added at -70 ° C and with stirring 1.3 mmol of 5-chloro-6- (5-chloropyrimidin-4-yl ) -3-formyl-7- (4-methylpiperidin-1-yl) pyrazolo [1,5-a] -pyrimidine. The mixture is stirred at room temperature for 15 hours, the solvent is distilled off under reduced pressure, and water is added to the residue.

The resulting mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and then the solvent is distilled off under reduced pressure. The residue is chromatographed with cyclohexane / ethyl acetate = 7: 3 on silica gel. Thus, 0.2 mmol of 5-chloro-6- (5-chloropyrimidin-4-yl) -3-ethenyl-7- (4-methylpiperidin-4yl) pyrazolo [1,5-a] pyrimidine is obtained.

HPLC: 1 d P = 4.70.

Example 76

100 mmol of 3-aminopyrazole and 100 mmol of 2- (5-chloropyrimidine-4yl) malonic acid dimethyl ester are added with stirring at room temperature in 27 ml of tri-nbutylamine. After the addition is complete, the reaction mixture is stirred for 3 hours with heating to 185 ° C. At the same time, methanol, which is formed during the interaction, is constantly distilled. It is then cooled to room temperature, the tri-n-butylamine is decanted, the residue is stirred with a mixture of isopropanol and methyl tert-butyl ether, and finally decanted. Under reduced pressure, the remaining residual solvent is distilled off. The 5,7-dihydroxy-6 (5-chloro-pyrimidin-4-yl) -pyrazolo [1,5-a] pyrimidine thus obtained is used without further purification for further interactions.

Example 77

A mixture consisting of 56 mmol of 5,7-dihydroxy-6- (5-chloropyrimidin-4-yl) pyrazolo [1,5-a] pyrimidine and 560 mmol of phosphoroxychloride is stirred for 30 minutes at 30 ° C, then cooled to 0 ° With and then added dropwise with stirring, 85 mmol of dimethylformamide. After graduation

- 26 009517 add the reaction mixture is continued to stir for another 12 hours at room temperature and then heated for 6 hours with reverse distillation. In conclusion, 56 mmol of phosphorus pentachloride is added to the reaction mixture and it is continued to be heated for another 12 hours during reverse distillation. After cooling to room temperature, the solvent is distilled off from the reaction mixture under reduced pressure, and then it is fed into ice-water. The resulting mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and then the solvent is distilled off under reduced pressure. The obtained 3-formyl-5,7-dichloro-8- (5-chloropyrimidin-4-yl) pyrazolo [1,5-a] pyrimidine is used without further purification for further syntheses.

Example A. Test for νοηΐιιπα (apple) / protective.

Solvent: 24.5 wt. acetone,

24.5 wt. including dimethylacetamide.

Emulsifier: 1 weight. including alkylaryl polyglycol ether.

To obtain a suitable formulation of the biologically active substance, 1 wt. including biologically active substances with the specified amounts of solvent and emulsifier and dilute the concentrate with water to the desired concentration.

To test the protective efficacy, young plants are sprayed with the formulation of the biologically active substance with the indicated consumable quantities. After drying, after spraying, the plants are inoculated with an aqueous suspension of conidia of the causative agent of apple scab νοηΐιιπα ίηass | ia115 and left in the incubation cabin for one day at about 20 ° C and 100% relative humidity.

Plants are placed in a greenhouse at a temperature of about 21 ° C and a relative humidity of about 90%.

10 days after the inoculation, an evaluation takes place. At the same time, 0% means efficiency, which corresponds to the control efficiency, while 100% efficiency means that no damage is observed.

In this test, the compounds according to this invention given in examples 1, 2, 3, 4 and 5 show an efficacy of over 90% with consumable amounts of 100 g / ha.

Example B. Test for VuYSCH (beans) / protective.

Solvent: 24.5 wt. acetone,

24.5 wt. including dimethylacetamide.

Emulsifier: 1 weight. including alkylaryl polyglycol ether.

To test the protective activity of young plants sprayed with the formulation of biologically active substances specified expenditure. After the plaque has dried after spraying, two small pieces of agar overgrown with boiled crocodile are placed on each leaf. Inoculated plants are placed in a darkened chamber at a temperature of about 20 ° C and a relative humidity of 100%.

2 days after inoculation, the amount of spots on the leaves corresponding to the attack is evaluated. At the same time, 0% means efficiency, which corresponds to the control efficiency, while 100% efficiency means that no damage is observed.

In this test, the compounds according to this invention given in examples 2, 3 and 5 show an efficiency in excess of 85% with consumable quantities of 500 g / ha.

Example C. Test for Riesssha (wheat) / protective.

Solvent: 50 wt. including Ν, Ν-dimethylacetamide.

Emulsifier: 1 weight. including alkylaryl polyglycol ether.

To test the protective activity of young plants sprayed with the formulation of biologically active substances specified expenditure. After the plaque has dried after spraying, the plants are sprayed with an aqueous suspension of conidia Risasha gesop6ya. Plants are left in the incubation cabin for 48 hours at a temperature of 20 ° C and a relative humidity of 100%.

The plants are then placed in a greenhouse at a temperature of about 20 ° C and a relative humidity of about 80%, in order to create favorable conditions for the development of rust pustules.

In this test, the compounds according to this invention given in examples 2 and 39 show an efficiency in excess of 85% with consumable quantities of 500 g / ha.

Example Ό. Test for Ro6o8räega (apple) / protective.

- 27 009517

Solvent: 24.5 wt. acetone,

24.5 wt. including dimethylacetamide.

Emulsifier: 1 weight. including alkylaryl polyglycol ether.

To test the protective activity of young plants sprayed with the formulation of biologically active substances with the specified expenditure. After drying of the plaque after spraying, the plants are inoculated with an aqueous suspension of spores of the pathogen of powdery mildew on the apple trees of Robokryaega leisopsypsya. Then the plants are placed in a greenhouse at a temperature of about 23 ° C and a relative humidity of about 70%.

In this test, the compounds of this invention given in examples 3 and 5 show an efficiency in excess of 90% with consumable amounts of 100 g / ha.

Example E. Test ίη uygo to determine ΕΌ ₅₀ microorganisms.

Solvent: methanol.

Emulsifier: alkylaryl polyglycol ether.

2 mg of the biologically active substance are mixed with 100 μl of methanol and then the concentrate, thus obtained, is diluted with a mixture of 1000 ml of methanol and 6 g of the above emulsifier to any desired concentration.

In cavitation (indentation) of microtiter plates, place 10 μl pipettes of the prepared preparation. After evaporation of the solvent, 200 μl of potato-dextrose medium will be placed in each well, to which the necessary concentration of spores, respectively, the micelles of the test microorganism, have been added. The resulting concentrations of biologically active substances in cavities are:

0.1 million shares, million shares, million shares,

100 million shares, respectively.

The resulting concentration of emulsifier is in each case 300 ppm.

For incubation, the microtiter plates are then placed for 3-5 days in a shaking device at 22 ° C and shaken until the necessary growth of the corresponding microorganisms is detected on the untreated control.

Assessment carried out photometrically at a wavelength of 620 nm. From the measurement results for various concentrations, the dose of the biologically active substance is determined, which leads to a 50 percent inhibition of the growth of fungi (ΕΌ ₅₀ ) compared to the untreated control.

According to this test, a value of ΕΌ ₅₀ for the compound according to this invention given in Example 1 with respect to Wojcik Schehea is achieved with a dose of a biologically active substance that is less than 10 ppm.

Claims

where B ¹ means alkyl containing 1-6 carbon atoms, which can be substituted once to five times, equally or differently by halogen, a cyano, hydroxy, alkoxy group containing 1-4 carbon atoms, and / or cycloalkyl containing 3- 6 carbon atoms, or

In ¹ means alkenyl containing 2-6 carbon atoms, which can be substituted once to three times, equally or differently by halogen, a cyano, hydroxy, alkoxy group containing 14 carbon atoms and / or cycloalkyl containing 3-6 carbon atoms , or

In ¹ means cycloalkyl containing 3-6 carbon atoms, which can be substituted from once to three times, the same or different halogen and / or alkyl containing 1-4 carbon atoms,

In ² means hydrogen or alkyl containing 1-4 carbon atoms, or

B ¹ and B ² together with the nitrogen atom to which they are attached mean saturated or not

- 28 009517 heterocyclic ring containing 3-6 atoms in the ring, and the heterocycle may additionally contain a nitrogen, oxygen or sulfur atom as an atom of the ring and can be substituted up to three times fluorine, chlorine, bromine, alkyl, containing 1-4 carbon atoms and / or haloalkyl containing 1-4 carbon atoms and 1-9 fluorine and / or chlorine atoms,

K ³ means a saturated or unsaturated heterocyclyl containing 5 or 6 atoms in the ring and 1-4 heteroatoms, such as nitrogen and / or sulfur, the heterocyclyl may be substituted once to four times, equally or differently with fluorine, chlorine, bromine, cyano- , nitro group, alkyl, alkoxy group, hydroxyiminoalkyl or alkoxyiminoalkyl with 1-3 carbon atoms in each alkyl part, haloalkyl or haloalkoxy group containing 1-3 carbon atoms and 1-7 halogen atoms, K ⁴ means hydrogen,

H1 is fluoro, chloro or bromo and

X is cyano, fluoro, chloro, bromo, iodo, formyl, alkenyl containing 2-6 carbon atoms, alkenyl containing 2-5 carbon atoms in the alkenyl moiety and substituted with a carboxy group, methoxycarbonyl or ethoxycarbonyl, alkoxycarbonyl containing 1-4 atoms in alkoxy part.

2. Pyrazolopyrimidines of the formula (I) according to claim 1, in which K ¹ means a radical of the formula and # means the point of attachment,

K ² means hydrogen, methyl, ethyl or propyl or

K ¹ and K ² together with the nitrogen atom to which they are attached mean pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 3,6-dihydro-1 (2H) -piperidinyl or tetrahydro-1 (2H) pyridazinyl, and these radicals may be substituted by 1-3 fluorine atoms, 1-3 methyl groups and / or trifluoromethyl, or

K ¹ and K ² together with the nitrogen atom to which they are attached mean a radical of the formula wherein K ′ is hydrogen or methyl,

K means methyl, ethyl, fluorine, chlorine or trifluoromethyl, t means the numbers 0, 1, 2 or 3, and K means the same or different radicals, if t means 2 or 3,

K 'means methyl, ethyl, fluorine, chlorine or trifluoromethyl and n means the numbers 0, 1, 2 or 3, and K' means the same or different radicals, if η means 2 or 3,

K ³ means pyridyl, which is attached at the 2 or 4 position and can be substituted once to four times, equally or differently with fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, methoxy, methylthio, hydroxyminomethyl, hydroxyminoethyl, methoxyminomethyl, methoxyiminoethyl and / or trifluoromethyl, or

K ³ means pyrimidyl, which is attached in the 2 or 4 position and can be substituted from once to three times, equally or differently with fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, methoxy, methylthio, hydroxyminomethyl, hydroxyminoethyl, methoxyminomethyl, methoxyiminoethyl and / or trifluoromethyl, or

K ³ means thienyl, which is attached in the 2 or 3 position and may be substituted by one

- 29 009517 up to three times, the same or different, with fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, methoxy, methylthio, hydroxyminomethyl, hydroxyiminoethyl, methoxyminomethyl, methoxyiminoethyl and / or trifluoromethyl, or

K ⁴ means hydrogen,

H1 is fluoro or chloro, and

X is cyano, fluoro, chloro, bromo, iodo, formyl or methoxycarbonyl, or

X is a radical of formula -CH = CH ₂ = _e y _ CH ₂ -CH = CH-CH ₃ CH ₃ '-CH = CH-C ₂ H _5, -C = CH-C ₂ H ₅ CH -CH = CH —Soon —CH — CH — CO — OCH, or —CH — CH — CO — CO — os ₂ n ₅ .

3. The method of obtaining pyrazolopyrimidines of the formula (I) according to claim 1, characterized in that the halopyrazolopyrimidines of the formula where

K ⁴ and Na1 have the meanings given in paragraph 1,

K ³ means pyridyl which is attached at the 2 or 4 position and may be substituted once to four times with trifluoromethyl, or

K ³ means pyrimidyl, which is attached in the 2 or 4 position and can be substituted from once to three times, the same or different fluorine and / or chlorine,

K ³ means thienyl, which is attached in the 2 or 3 position and can be substituted once to three times by chlorine or methyl,

X ¹ means a cyano group or formyl, and

Υ ¹ means halogen, is reacted with amines of the formula ¥ H where

K ¹ and K ² have the meanings given in claim 1, if necessary in the presence of a diluent, if necessary in the presence of an acid acceptor and, if necessary, in the presence of a catalyst.

4. Means for combating unwanted microorganisms, characterized in that it contains at least one pyrazolopyrimidine of the formula (I) according to claim 1 or 2, along with fillers and / or surfactants.

5. The use of pyrazolopyrimidines of the formula (I) according to claim 1 or 2 for controlling undesirable microorganisms.

6. A method for controlling undesirable microorganisms, characterized in that the pyrazolopyrimidines of the formula (I) according to claim 1 or 2 are applied to undesirable microorganisms and / or to their living environment.

7. A method of obtaining funds for combating unwanted microorganisms, characterized in that the fillers and / or surfactants are mixed with pyrazolopyrimidines of the formula (I) according to claim 1 or 2.

8. Halopyrazolopyrimidines of the formula wherein K ³ is pyridyl which is attached at the 2- or 4-position and may be substituted from

- 30 009517 once to four times with trifluoromethyl, or

B ³ means pyrimidyl which is attached at the 2- or 4-position and can be substituted once to three times, equally or differently with fluorine and / or chlorine, or

In ³ means thienyl, which is attached in the 2- or 3-position and can be substituted from once to three times by chlorine or methyl,

B ⁴ means hydrogen, H1 means halogen,

X ¹ means a cyano group, formyl or alkoxycarbonyl containing 1-4 carbon atoms in the alkoxy part, and

Υ ¹ means halogen.

9. The method of producing halopyrazolopyrimidines of the formula (II) according to claim 8, characterized in that the hydroxypyrazolopyrimidines of the formula he

where B ³ and B ⁴ have the meanings given in clause 8, and

B means cyano or alkoxycarbonyl containing 1-4 carbon atoms in the alkoxy part, is reacted with halogenating agents if necessary in the presence of a diluent.

10. The method of obtaining halopyrazolopyrimidines of the formula (II) according to claim 8, in which X ¹ means formyl, characterized in that hydroxypyrazolopyrimidines of the formula where

B ³ and B ⁴ have the meanings given in paragraph 8, are reacted with phosphoroxychloride in the presence of dimethylformamide and, if necessary, with the addition of phosphorus pentachloride.

11. Hydroxypyrazolopyrimidines of the formula where In ³ has the meaning specified in paragraph 8,

B ⁴ means hydrogen, and

B means a cyano group or alkoxycarbonyl containing 1-4 carbon atoms in the alkyl part.

12. The method of obtaining hydroxypyrazolopyrimidines of the formula (X) according to claim 11, characterized in that the heterocyclyl malone ester of the formula

COOP ¹² K ³ - ((XII),

COOP ¹² where B ³ has the meanings given in clause 11, and

B ¹² means alkyl containing 1-4 carbon atoms, is reacted with aminopyrazoles of the formula where B ⁴ and B have the meanings given in clause 11, if necessary in the presence of a diluent and, if necessary, in the presence of an acid binding agent.

13. The pyridyl malonic ester of the formula where

B ¹² means alkyl containing 1-4 carbon atoms,

¹³ means haloalkyl containing 1-4 carbon atoms.

- 31 009517

14. The method of producing pyridylmalonic esters of the formula (ΧΙΙ-a) according to item 13, wherein the halo-pyridines of the formula (XIV), where

B ¹³ has the meanings given in clause 13, and

Υ ² means halogen, is reacted with malonic esters of the formula

COOC ¹² where B ¹² has the meanings given in clause 13, if necessary in the presence of a diluent, if necessary in the presence of a copper salt and, if necessary, in the presence of an acid acceptor.

15. Pyrimidyl malonic ester of the formula where B ¹² means alkyl containing 1-4 carbon atoms,

¹⁴ means halogen and

At ¹⁵ and B ¹⁶ each means hydrogen.

16. The method of producing pyrimidylmalonic esters of the formula (X11-b) according to clause 15, wherein the halo pyrimidines of the formula wherein B ¹⁴ , B ¹⁵ and B ¹⁶ have the meanings given in clause 15, and

Υ ³ means halogen react with malonic esters of the formula

COOC ¹² where B ¹² has the meanings given in clause 15, if necessary in the presence of a diluent, if necessary in the presence of a copper salt and, if necessary, in the presence of an acid acceptor.