Compound, containing pyridine ring, and method of obtaining halogenated picoline derivative and tetrazolyloxime derivative

FIELD: chemistry.

SUBSTANCE: invention relates to compound, which contains pyridine ring, represented by formula (1) , where R0 represents C1-6alkoxygroup, C1-6alkoxy-C1-6alkoxygroup, C1-6alkoxy-C1-6alkyl group, 1,3-dioxan-2-yl-C1-6alkyl group or group CR01C(=NOR02) (where each of R01 and R02 independently represents C1-6alkyl group), R1 represents C1-2 alkoxycarbonyl group, acetyl group or benzoyl group, which can be substituted with nitrogroup, X represents halogen atom, and n represents quantity of X substituents and equals integer number from 0 to 3, and when n equals 2 or more, X substituents can be similar or different from each other, which can be synthesised in industrially profitable way and used as intermediate compound for obtaining tetrazolyloxime derivatives which demonstrate fungicidal activity.

EFFECT: industrially profitable methods of obtaining tetrazolyloxime derivatives are described.

10 cl, 3 tbl, 13 ex

 

The technical field to which the invention relates.

The present invention relates to (1) the compound containing a pyridine ring, which is ideal agrochemical intermediate compound (2) method, which enables to obtain a high yield of 2-substituted derivative amino-6-halogenopyrimidines, useful for use as a synthetic intermediate for agrochemicals and the like, and (3) industrial best way of deriving tetrasociological, which shows the superior antagonistic properties against plant diseases.

Priority is claimed on the application for Japan patent No. 2010-056718 filed March 12, 2010, the application for the Japan patent No. 2010-127201, filed June 2, 2010, and the patent application of Japan No. 2010-115703, filed may 19, 2010, the contents of which are incorporated into this description by reference.

The level of technology

Examples of methods for obtaining derivatives of halogenopyrimidines include the method disclosed in non-examination of the patent application Japan, first published under No. Hei 08-259539 (patent document 1)in which 2-chloro-5-chloromethylpyridine is produced by adding dropwise glorieuses agent, such as oxacillin, 2-chloro-5-acetaminophenodeine in a solution of acetonitrile and dimethylformamide, and postheating is receiving the mixture at 80°C.

Non-examination of the patent application Japan, first published under No. Hei 07-017948 (patent document 2), discloses a method of producing chloromethylpyridine due to the interaction of aminomethylpyridine with nitrotyrosine agent or diastereomer agent in the presence of a diluent and if appropriate in the presence of hydrogen chloride at a temperature in the range from -20°C to +50°C.

Next, a non-examination of the patent application Japan, first published under No. Sho 56-43268 (patent document 3), discloses a method of obtaining 6-chloro-2-(chloromethyl)pyridine, which includes the recovery of 6-chloro-2-(trichloromethyl)pyridine or 6-chloro-2-(dichloromethyl)pyridine.

Derivatives tetrasociological described in a non-examination of the patent application Japan, first published under No. 2003-137875 (patent document 4), and similar documents, exhibit excellent fungicidal activity and are considered prospective for active ingredients, agents for control of plant diseases. The way that was described for obtaining such derivatives tetrasociological includes interaction derived tetrachlormethane represented by the formula (A)with hydroxylamine to obtain a derived tetraallyloxyethane represented by the formula (V), and the subsequent interaction about wodnego tetraallyloxyethane connection, represented by formula (C), in the presence of a base with obtaining, thus, derived tetrasociological represented by the formula (D).

In relation to the present invention patent documents 1-3 describe how to obtain derivatives of halogenopyrimidines. Further, patent documents 4 and 5 describe derivatives tetrasociological having a structure similar to that of compounds of the present invention, and such derivative tetrasociological have been proposed for use as fungicides.

Disclosure of inventions

Tasks solved in the present invention

The aim of the present invention is (1) a compound containing a pyridine ring, which is ideal agrochemical intermediate compound, (2) a method which enables to obtain a high yield of 2-substituted derivative amino-6-glomerella, useful for use as a synthetic intermediate for agrochemicals and the like, and (3) industrial-effective way of deriving tetrasociological exhibiting excellent antagonistic properties against plant diseases.

Means to solve this task

The authors of the present invention conducted intensive research aimed at achieving the above objectives. In the result, the authors of the present invention have found, (1) connection of some specific structure containing a pyridine ring, can be obtained commercially beneficial manner and used as intermediate compounds in obtaining derived tetrasociological exhibiting fungicidal activity, (2) by the reaction of 2-substituted derivative amino-6-methylpyridine and brainwashes agent in an organic solvent with subsequent interaction of the thus obtained reaction product with a complex ester of phosphorous acid and a base in an organic solvent can be a high yield is obtained 2-substituted derivative amino-6-pommerellen, and (3) the specific interaction of 2-amino substituted derivative-6-halogenopyrimidines and derived tetraallyloxyethane can be obtained a new intermediate compound consisting of derived tetrasociological, and in the interaction of specific 2-substituted derivative amino-6-glomerella and derived tetraallyloxyethane, followed by treatment of the thus obtained reaction product with base, can be industrially advantageous way derived tetrasociological exhibiting excellent antagonistic activity against plant diseases. The present invention has been made in the clause is Ogadenia additional research on the basis of these discoveries.

In other words, the present invention includes the aspects described below.

[1] the Compound containing a pyridine ring represented by the formula (1):

where R0represents a C1-6alkoxygroup, C1-6alkoxy-C1-6alkoxygroup, C1-6alkoxy-C1-6alkyl group, 1,3-dioxane-2-yl-C1-6alkyl group or CR01C(=NOR02) group (where each R01and R02independently represents a C1-6alkyl group),

R1represents a C1-2alkoxycarbonyl group, acetyl group or benzoyloxy group which may be substituted by a nitro-group,

Z represents a halogen atom, a cyano, a nitro-group, a hydroxyl group, Tilney group, formyl group, carboxyl group, unsubstituted or substituted by an amino group, unsubstituted or substituted alkyl group, unsubstituted or substituted alkenylphenol group, unsubstituted or substituted alkylamino group, unsubstituted or substituted aryl group, unsubstituted or substituted heterocyclic group, OR3, S(O)pR3, COR3or CO2R3(where R3represents an unsubstituted or substituted by an amino group, unsubstituted or substituted alkyl group, unsubstituted or substituted alkenyl the ing group, unsubstituted or substituted alkylamino group, unsubstituted or substituted aryl group or unsubstituted or substituted heterocyclic group, and R represents the number of oxygen atoms, given in parentheses, and is an integer from 0 to 2),

m represents the number of substituents Z and an integer from 0 to 3, and when m is 2 or more, the substituents Z may be the same or different from each other,

X represents a halogen atom, and

n represents the number of substituents X and is an integer from 0 to 3, and when n is 2 or more, the substituents X may be the same or different from each other.

[2] a method of obtaining a halogenated derivative of picoline represented by the formula (3), including stage B1 of the interaction of compounds represented by formula (2), and halogenation agent in an organic solvent, and phase B2 recovery of the reaction product obtained in stage B1,

where R1brepresents an unsubstituted or substituted alkoxycarbonyl group,

R2brepresents an unsubstituted or substituted alkoxycarbonyl group, unsubstituted or substituted acyl group, unsubstituted or substituted aryloxyalkyl group, unsubstituted or substituted heterocyclics the Yu-oxycarbonyl group,

Z represents a halogen atom, a cyano, a nitro-group, a hydroxyl group, Tilney group, formyl group, carboxyl group, unsubstituted or substituted by an amino group, unsubstituted or substituted alkyl group, unsubstituted or substituted alkenylphenol group, unsubstituted or substituted alkylamino group, unsubstituted or substituted aryl group, unsubstituted or substituted heterocyclic group, OR3, S(O)pR3, COR3or CO2R3(where R3represents an unsubstituted or substituted by an amino group, unsubstituted or substituted alkyl group, unsubstituted or substituted alkenylphenol group, unsubstituted or substituted alkylamino group, unsubstituted or substituted aryl group or unsubstituted or substituted heterocyclic group, and R represents the number of oxygen atoms, given in parentheses, and is an integer from 0 to 2),

m represents the number of substituents Z and an integer from 0 to 3, and when m is 2 or more, the substituents Z may be the same or different from each other,

where R1b, R2b, Z and m are the same as defined above, and X represents a halogen atom.

[3] a method of obtaining a halogenated derivative of picoline in soo is according to [2], above, where stage B1 is performed in the presence of a base.

[4] a method of obtaining a halogenated derivative of picoline in accordance with [2] or [3]above, where the organic solvent at the stage B1 is a benzene or halogenated hydrocarbons.

[5] a method of obtaining a halogenated derivative of picoline in accordance with [2] or [3]above, where stage B2 is performed in the presence of a phase transfer catalyst.

[6] a method of obtaining a halogenated derivative of picoline in accordance with [2] or [3]above, where the halogenation agent is pomeroyi agent, and X represents a bromine atom.

[7] the Method of obtaining the brominated derivative picoline, represented by the formula (6), including the interaction of the brominated derivative picoline, represented by the formula (4) and/or formula (5), a complex ester of phosphorous acid and a base in an organic solvent,

where R1brepresents an unsubstituted or substituted alkoxycarbonyl group,

R2brepresents an unsubstituted or substituted alkoxycarbonyl group, unsubstituted or substituted acyl group, unsubstituted or substituted aryloxyalkyl group, or unsubstituted or substituted the th heterocyclic-oxycarbonyl group,

Z represents a halogen atom, a cyano, a nitro-group, a hydroxyl group, Tilney group, formyl group, carboxyl group, unsubstituted or substituted by an amino group, unsubstituted or substituted alkyl group, unsubstituted or substituted alkenylphenol group, unsubstituted or substituted alkylamino group, unsubstituted or substituted aryl group, unsubstituted or substituted heterocyclic group, OR3, S(O)pR3, COR3or CO2R3(where R3represents an unsubstituted or substituted by an amino group, unsubstituted or substituted alkyl group, unsubstituted or substituted alkenylphenol group, unsubstituted or substituted alkylamino group, unsubstituted or substituted aryl group or unsubstituted or substituted heterocyclic group, and R represents the number of oxygen atoms, given in parentheses, and is an integer from 0 to 2), and

m represents the number of substituents Z and an integer from 0 to 3, and when m is 2 or more, the substituents Z may be the same or different from each other.

[8] the Method of deriving tetrasociological represented by the formula (10), including the state S1 interaction halogenated derivative picoline, represented by the formula (7), with the derived tet is analysetechniken, represented by the formula (8), to obtain the derived tetrasociological represented by the formula (9), and stage C2 processing derived tetrasociological represented by the formula (9) and obtained at the stage S1, the base

where in the formula (7) R1Crepresents an unsubstituted or substituted alkyl group or unsubstituted or substituted alkoxygroup,

R2Crepresents an unsubstituted or substituted alkoxycarbonyl group or unsubstituted or substituted acyl group,

X represents a halogen atom,

Z represents a halogen atom, a cyano, a nitro-group, a hydroxyl group, Tilney group, formyl group, carboxyl group, unsubstituted or substituted by an amino group, unsubstituted or substituted alkyl group, unsubstituted or substituted alkenylphenol group, unsubstituted or substituted alkylamino group, unsubstituted or substituted aryl group, unsubstituted or substituted heterocyclic group, OR3, S(O)pR3, COR3or CO2R3(where R3represents an unsubstituted or substituted by an amino group, unsubstituted or substituted alkyl group, unsubstituted or substituted alkenylphenol group, unsubstituted or substituted alkylamino group, nezametnoye substituted aryl group, or unsubstituted or substituted heterocyclic group, and R represents the number of oxygen atoms, given in parentheses, and is an integer from 0 to 2), and

m represents the number of substituents Z and an integer from 0 to 3, and when m is 2 or more, the substituents Z may be the same or different from each other, and

in the formula (8) Y is an unsubstituted or substituted alkyl group,

Rather it represents a halogen atom, unsubstituted or substituted alkyl group, unsubstituted or substituted alkoxygroup, cyano, unsubstituted or substituted alkylsulfonyl group, a nitrogroup, or unsubstituted or substituted aryl group, and

ncrepresents the number of substituents and is an integer from 0 to 5, and when ncis 2 or more, the substituents may be identical or different from each other.

[9] Derived tetrasociological represented by the formula (9):

where R1Crepresents an unsubstituted or substituted alkyl group or unsubstituted or substituted alkoxygroup,

R2Crepresents an unsubstituted or substituted alkoxycarbonyl group or unsubstituted or substituted acyl group,

Z represents a halogen atom, cyano, nitro is the SCP, hydroxyl group, Tilney group, formyl group, carboxyl group, unsubstituted or substituted by an amino group, unsubstituted or substituted alkyl group, unsubstituted or substituted alkenylphenol group, unsubstituted or substituted alkylamino group, unsubstituted or substituted aryl group, unsubstituted or substituted heterocyclic group, OR3, S(O)pR3, COR3or CO2R3(where R3represents an unsubstituted or substituted by an amino group, unsubstituted or substituted alkyl group, unsubstituted or substituted alkenylphenol group, unsubstituted or substituted alkylamino group, unsubstituted or substituted aryl group or unsubstituted or substituted heterocyclic group, and R represents the number of oxygen atoms, given in parentheses, and is an integer from 0 to 2),

m represents the number of substituents Z and an integer from 0 to 3, and when m is 2 or more, the substituents Z may be the same or different from each other, and

Y is an unsubstituted or substituted alkyl group,

Rather it represents a halogen atom, unsubstituted or substituted alkyl group, unsubstituted or substituted alkoxygroup, cyano, unsubstituted or substituted alkylsulfonyl group, nor is regroupe or unsubstituted or substituted aryl group, and

ncrepresents the number of substituents and is an integer from 0 to 5, and when ncis 2 or more, the substituents may be identical or different from each other.

[10] the Method of deriving tetrasociological represented by the formula (9), including the state S1 interaction halogenated derivative picoline, represented by the formula (7), with the derived tetraallyloxyethane represented by the formula (8)

where R1Crepresents an unsubstituted or substituted alkyl group or unsubstituted or substituted alkoxygroup,

R2Crepresents an unsubstituted or substituted alkoxycarbonyl group or unsubstituted or substituted acyl group,

X represents a halogen atom,

Z represents a halogen atom, a cyano, a nitro-group, a hydroxyl group, Tilney group, formyl group, carboxyl group, unsubstituted or substituted by an amino group, unsubstituted or substituted alkyl group, unsubstituted or substituted alkenylphenol group, unsubstituted or substituted alkylamino group, unsubstituted or substituted aryl group, unsubstituted or substituted heterocyclic group, OR3, S(O)pR3, COR3or CO2R3(where R3p is ecstasy an unsubstituted or substituted by an amino group, unsubstituted or substituted alkyl group, unsubstituted or substituted alkenylphenol group, unsubstituted or substituted alkylamino group, unsubstituted or substituted aryl group or unsubstituted or substituted heterocyclic group, and R represents the number of oxygen atoms, given in parentheses, and is an integer from 0 to 2),

m represents the number of substituents Z and an integer from 0 to 3, and when m is 2 or more, the substituents Z may be the same or different from each other,

Y is an unsubstituted or substituted alkyl group,

Rather it represents a halogen atom, unsubstituted or substituted alkyl group, unsubstituted or substituted alkoxygroup, cyano, unsubstituted or substituted alkylsulfonyl group, a nitrogroup, or unsubstituted or substituted aryl group, and

ncrepresents the number of substituents and is an integer from 0 to 5, and when ncis 2 or more, the substituents may be identical or different from each other.

The results of the inventions

The compound containing a pyridine ring, according to the present invention can be synthesized industrially advantageous way and used as intermediate compounds for obtaining derivatives of tetrazoles is Shem, exhibiting fungicidal activity. Furthermore, the method of obtaining of the present invention allows high selectivity and high yield 2-substituted derivatives of amino-6-glomerella and enables industrial best way to obtain derivatives tetrasociological with excellent antagonistic properties against plant diseases.

The implementation of the invention

1. The compound containing the pyridine ring, which is ideal as agrochemical intermediate connection

The compound containing the pyridine ring, in accordance with the present invention is a compound represented by the formula (1).

The connection can be synthesized as described below.

In the case when n=0,

where R0, R1, Z and m are as described above, and L represents a leaving group such as halogen atom.

The compound represented by formula (12), according to the present invention (hereinafter referred to as "compound (12)) can be obtained by treating compound represented by the formula (11) (hereinafter referred to as "compound (11)"), a compound represented by the formula, R1-L. L is a leaving group such as halogen atom.

Examples of compounds, n is redstavleny R 1-L, include methoxycarbonylamino, ethoxycarbonylphenyl, acetylchloride, benzoyl chloride and p-nitrobenzoate.

In the case where n=1-3,

where R0, R1, Z, m and X are as described above and n' is an integer from 1 to 3.

The compound represented by the formula (13), according to the present invention (hereinafter referred to as "compound (13)) can be obtained by halogenoalkanes connection (12). The halogenation reaction can be carried out using traditional methods.

In the reaction of halogenation can be used a simple halogen, sulfurylchloride, pentachloride phosphorus, N-chlorosuccinimide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, anhydrous copper chloride, aluminium chloride or the like

R0in the compound (1) according to the present invention represents a C1-6alkoxy group, a C1-6alkoxy-C1-6alkoxy group, a C1-6alkoxy-C1-6alkyl group, 1,3-dioxane-2-yl-C1-6alkyl group or CR01C(=NOR02) group (where each R01and R02independently represent C1-6alkyl group).

Examples of C1-6alkoxygroup for R0include a methoxy group, ethoxypropan, n-propoxylate, out-propoxylate, n-butoxypropyl, out-butoxypropyl, sec-butoxypropyl, tert-butoxy the PPU, n-pentyloxy and n-hexyloxy.

Examples of C1-6alkoxy-C1-6alkoxygroup for R0include methoxyethoxy, ethoxyethoxy, methoxyethoxy, 3-ethoxypropanol, 2-toxinotype, 4-butoxyethoxy, 1-butoxyethoxy, 3 isopropoxy-2-methylpropoxy and 1-methoxy-2-ethoxyethoxy.

Examples of C1-6alkoxy-C1-6alkyl groups for R0include methoxymethyl group, ethoxymethyl group, methoxyamino group, methoxypropyl group, ethoxymethylene group, methoxybutyl group, methoxyamino group, propoxyethyl group, 2-methoxy-1,1-dimethylethylene group, 1-ethoxy-1-methylamino group and 1 ethoxy-2-methoxyaniline group.

Examples of 1,3-dioxane-2-yl-C1-6alkyl groups for R0include 1,3-dioxane-2-ylmethylene group and 1,3-dioxane-2-ratelow group.

Each of R01and R02in the group of CR01C(=NOR02for R0independently represents a C1-6alkyl group such as methyl group, ethyl group, n-sawn group, ISO-sawn group, n-bucilina group or n-exilda group.

Specific examples of groups CR01C(=NOR02for R0include CH3C(=NON3), CH3C(=NOC3H7and C2H5C(=NOCH3).

R11-2alkoxycarbonyl group, acetyl group or benzoyloxy group which may be substituted by a nitro-group.

Examples1-2alkoxycarbonyl groups for R1include methoxycarbonyl group and ethoxycarbonyl group.

Examples benzoline groups which may be substituted by a nitro-group for R include n-nitrobenzoyl group.

In addition, Z and m in the formula (1), the formula (12) and the formula (13) are the same as Z and m, are described below for the formula (7).

X in the formula (1) represents a halogen atom, and examples of halogen atoms include fluorine atom, chlorine atom, bromine atom and iodine atom. From these values, a chlorine atom or a bromine atom are preferable, and a bromine atom is preferable.

Connection (1) according to the present invention is used as intermediate compounds for deriving tetrasociological, which exhibits fungicidal activity.

2. The method, which produces a high yield of 2-substituted derivatives amino-6-halogenopyrimidines useful when used as a synthetic intermediate for agrochemicals, etc..

A method of obtaining a halogenated derivative of picoline is according to the present invention includes a step B1 of the interaction of compounds represented by formula (2), and halogenation agent in an organic solvent, and phase B2 recovery of the reaction product obtained in stage B1.

[Stage B1]

The original substance used in the production method of the present invention is a compound represented by the formula (2).

R1bin the formula (2) represents an unsubstituted or substituted alkoxycarbonyl group. The Deputy has no particular restrictions, provided that the Deputy is inactive in the reaction of halogenation. Alkoxygroup in alkoxycarbonyl group preferably contains 1 to 6 carbon atoms.

Specific examples of unsubstituted alkoxycarbonyl groups for R1binclude methoxycarbonyl group, ethoxycarbonyl group, ISO-propoxycarbonyl group, n-propoxycarbonyl group, n-butoxycarbonyl group, ISO-butoxycarbonyl group, sec-butoxycarbonyl group and tert-butoxycarbonyl group.

Examples of substituted alkoxycarbonyl groups for R1binclude cinematically group, 1-cyanoethoxyphosphinyl group, 2-cyanoethoxyphosphinyl group, micrometeorology group, chloromethoxybanned group, formicoxenini group, deformationally group, crypto methoxycarbonyl group, 2-forecastable group, 2,2,2-triftoratsetofenona group, methoxyethoxymethyl group, ethoxymethyleneamino group, 1-methoxyethoxymethyl group, 2-methoxyethoxymethyl group and 2-glaretexturesresident group.

Among these substituents R1brepresents preferably unsubstituted alkoxycarbonyl group, more preferably unsubstituted alkoxycarbonyl group, in which alkoxygroup contains 1 to 6 carbon atoms, and most preferably tert-butoxycarbonyl group.

R2bin the formula (2) represents an unsubstituted or substituted alkoxycarbonyl group, unsubstituted or substituted acyl group, unsubstituted or substituted aryloxyalkyl group or unsubstituted substituted heterocyclic oxycarbonyl group.

Examples of unsubstituted alkoxycarbonyl groups for R2binclude methoxycarbonyl group, ethoxycarbonyl group, ISO-propoxycarbonyl group, n-propoxycarbonyl group, n-butoxycarbonyl group, ISO-butoxycarbonyl group, sec-butoxycarbonyl group and tert-butoxycarbonyl group.

Examples of substituted alkoxycarbonyl groups for R2binclude cinematically group, 1-cyanoethoxyphosphinyl the group, 2-cyanoethoxyphosphinyl group, micrometeorology group, chloromethoxybanned group, formicoxenini group, deformationally group, triphtalocyaninine group, 2-forecastable group, 2,2,2-triftoratsetofenona group, methoxyethoxymethyl group, ethoxymethyleneamino group, 1-methoxyethoxymethyl group, 2-methoxyethoxymethyl group and 2-glaretexturesresident group.

Acyl group for R2brepresents a group in which a hydrogen atom or an alkyl group, Alchemilla group, Alchemilla group, aryl group or heterocyclic group linked to a carbonyl group.

Examples of unsubstituted acyl groups include formyl group; alkylcarboxylic groups such as acetyl group, propylaniline group, n-propellerblade group, n-butylcellosolve group, octonaria group, ISO-propellerblade group, ISO-butylcellosolve group, pivellina group and isovaleryl group; alkenylamine groups, such as calolina group and methacryloyl group; alkylcarboxylic groups, such as Propylamine group; arylcarbamoyl groups, such as benzoline group; and a heterocyclic carbonyl group such as 2-pyridylcarbonyl group is a and taylorsville group.

Examples of substituted acyl groups for R2binclude porazitelnuyu group, chloroacetyl group, nitroaniline group, cyanoacetylene group, methoxyacetyl group, dibromoethylene group, trifluoracetyl group, trichloroethylene group, tribromoaniline group, 3,3,3-triphosphopyridine group, 3,3,3-trichloropyridinol group, 2,2,3,3,3-pentafluoropropanol group and 4-chlorobenzoyloxy group.

Examples of unsubstituted aryloxyalkyl groups for R2binclude vinyloxycarbonyl group, 1-naphthalocyanine group, 2-naphthalocyanine group, ashleysexygirl group, interracialporno group, intenlational group and tetrahydrocarboline group.

Examples of substituted aryloxyalkyl groups for R2binclude 6-methylenedioxyaniline group, 4-methylenedioxyaniline group, 4-fortuneloungeonline group, 4-chlorpheniramineodeine group, 2,4-dichlorhydroxyquinoleine group, 3,4-dichlorhydroxyquinoleine group, 3,5-dichlorhydroxyquinoleine group, 2,6-divertidoctioning group, 4-triftormetilfullerenov group, 4-methoxyphenylacetylene group, 3,4-dimethoxyphenylacetone group, 3,4-methylenedioxyphenylacetone group, 3-phenoxyphenoxy ebonyjoy group, 4-cryptonetxdeviceevent group and 4-methoxy-1-naphthalocyanine group.

Examples of the unsubstituted heterocyclic oxycarbonyl groups for R2binclude unsaturated heterocyclic 5-membered ring oxycarbonyl groups such as furan-2-intoxicatingly group, furan-3-intoxicatingly group, thiophene-2-intoxicatingly group, thiophene-3-intoxicatingly group, pyrrol-2-intoxicatingly group, pyrrol-3-intoxicatingly group, oxazol-2-oxycarbonyl group, oxazol-4-intoxicatingly group, oxazol-5-intoxicatingly group, a thiazol-2-intoxicatingly group, thiazol-4-intoxicatingly group, thiazol-5-intoxicatingly group, isooxazolyl-3-ylcarbonyl group, isooxazolyl-4-intoxicatingly group, isooxazolyl-5-intoxicatingly group, isothiazol-3-intoxicatingly group, isothiazol-4-intoxicatingly group, isothiazol-5-intoxicatingly group, imidazol-2-intoxicatingly group, imidazol-4-intoxicatingly group, imidazol-5-intoxicatingly group, a pyrazole-3-intoxicatingly group, pyrazole-4-intoxicatingly group, a pyrazole-5-intoxicatingly group, 1,3,4-oxadiazol-2-intoxicatingly group, 1,3,4-thiadiazole-2-intoxicatingly group, 1,2,3-triazole-4-intoxicatingly group, 1,2,4-triazole-3-iloxi Bonilla group and 1,2,4-triazole-5-intoxicatingly group; unsaturated heterocyclic 6-membered ring oxycarbonyl groups, such as pyridine-2-intoxicatingly group, pyridine-3-intoxicatingly troupe, pyridine-4-intoxicatingly group, 5-chloro-3-pyridylcarbonyl group, 3-trifluoromethyl-2-pyridylcarbonyl group, pyridazin-3-intoxicatingly group, pyridazin-4-intoxicatingly group, pyrazin-2-intoxicatingly group, pyrimidine-5-intoxicatingly group, 1,3,5-triazine-2-intoxicatingly group and 1,2,4-triazine-3-intoxicatingly group; and saturated or partially unsaturated heterocyclic oxycarbonyl groups, such as tetrahydrofuran-2-intoxicatingly group, tetrahydropyran-4-intoxicatingly group, piperidine-3-intoxicatingly group, pyrrolidin-2-intoxicatingly group, morpholino-oxycarbonyl group, piperidino-oxycarbonyl group, piperazine derivatives-oxycarbonyl group, N-methylpiperazine-oxycarbonyl group, aziridine-oxycarbonyl group, azetidine-oxycarbonyl group, pyrrolidino-oxycarbonyl group and oxazoline-2-intoxicatingly group.

Examples of substituted heterocyclic oxycarbonyl groups for R2binclude 3-triptorelin-2-intoxicatingly group, 4-triptoreline-2-pyridylcarbonyl group, 3-methyl-1-pyrazolines the carbonyl group, 4-trifluoromethyl-1-imidazolidinecarboxamide group and 3,4-debtorprovidian-oxycarbonyl group.

Among these groups, R2bin the formula (2) preferably represents unsubstituted or substituted benzoyloxy group. The Deputy bentilee group there are no particular restrictions, provided that the Deputy is inactive in the reaction of halogenation.

Specific examples of substituted benzoline groups for R2binclude 2,6-dimethoxybenzoyl group, 3,5-nitrobenzoyl group, 2,4,6-trichlorobenzoyl group and 4-chlorobenzoyloxy group.

Z and m in the formula (2) are the same as Z and m, are described below for the formula (7).

In respect of halogenation agent used in stage B1, there is no particular limitation and can be used any compound that is normally used for halogenation,.

Examples of the halogenation agent include compounds, which themselves function as halogenation agents, and compounds that turn into a halogenation agent in the reaction system. Specific examples of halogenation agents include bromine (Br2), chlorine (Cl2), bromovalerate, chloride; bromides of metals, such as lithium bromide, potassium bromide, sodium bromide, magnesium bromide, calcium bromide, barium bromide, aluminum bromide, t is bromide phosphorus and pentabromide phosphorus; the bromide of ammonium, such as ammonium bromide, the bromide of Tetramethylammonium, bromide of tetraethylammonium and bromide, Tetra-n-butylamine; and trimethylsilylpropyne, BrF, BrF3, BrF5, BrCl, BrCl3, bromo-pyridine complex, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-diiodo-5,5-dimethylhydantoin, thienylboronic, hypochlorites, hypobromites, the acid chloride cyanuric acid, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS), dimethyldichlorosilane and trichloroisocyanurate acid. Among the above compounds, preferred are brainwashee agents, and dimethylpiperidino is especially preferred.

Although no particular restrictions regarding the number of halogenation agent is not imposed, the number of atoms of halogen per 1 mol of compound represented by formula (2)preferably is in the range from 0.1 to 10 moles, and more preferably in the range from 1 to 5 moles.

Examples of organic solvents used in stage B1, include ethers, such as diethyl ether, butyl methyl ether, tetrahydrofuran, dioxane and dimethoxyethane; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachlorethane, dichloroethane, trichloroethane and dichloroethylene; aromatic hydrocarbons such as benzene, toluene and KSIL is l; aliphatic hydrocarbons such as pentane, hexane, heptane, octane and cyclohexane; esters such as methyl acetate, ethyl acetate and propyl; polar aprotic solvents, such as acetone, methyl ethyl ketone, cyclohexanone, acetonitrile, propionitrile, N,N-dimethylformamide, dimethylsulfoxide, triamide hexamethylphosphoric acid, sulfolane, dimethylacetamide and N-organic; proton solvents, such as acetic acid; and water.

Of these compounds, from the viewpoint of suppression of side reactions and provide selective halogenation of a methyl group in the compound represented by formula (2), preferred is a benzene or halogenated hydrocarbons.

In the present invention stage B1 is preferably carried out in the presence of a base. In the presence of base in the reaction system side reactions are suppressed, and halogenoalkane methyl group in the compound represented by formula (2), proceeds with the best selectivity.

Examples of bases include hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide; hydroxides of alkaline earth metals, such as magnesium hydroxide and calcium hydroxide; carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate;

g is tidy, such as sodium hydride and calcium hydride; alkoxides of metals such as sodium methoxide, ethoxide sodium and magnesium methoxide; and organic bases such as triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, 4-(dimethylamino)pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo[4.3.0]non-5-ene. Any connection of these bases may be used alone or may be used in combination of two or more bases. Among the above-mentioned reason, it is preferable to sodium bicarbonate.

The amount of base is preferably in the range from 0.1 to 10 moles, and more preferably in the range from 0.5 to 2 moles per 1 mole of the compound represented by formula (2).

In relation to the execution order, etc. taken for the reaction between the compound represented by formula (2) and halogenation agent, no particular limitation is imposed. For example, the compound represented by formula (2), and, if necessary, sodium bicarbonate, may be added in an organic solvent and then to the reaction mixture gradually add halogenation agent to continue the reaction. The temperature during the period of time from the beginning of the reaction until completion of the reaction can either be supported by Kee is Noah temperature, or to vary, but preferably the temperature is in the range from 0 to 200°C., and more preferably in the range from room temperature to 150°C.

When conducting stage B1 metal group in the compound represented by formula (2), selectively halogenous. The result is the reaction product containing monohalogenated derived picoline, represented by the formula (3), dihalogenoalkane derived picoline, represented by the formula (14), and/or trihalomethane derived picoline, represented by the formula (15). The direction of the reaction product on purification by traditional methods in order to highlight monohalogenated derived picoline, represented by the formula (3), with a high degree of purity, requires considerable cost and time. Accordingly, according to the present invention perform stage B2 described below.

Regarding the method used to restore the mixed reaction product containing the compound represented by formula (3), formula (14) and formula (15)obtained in stage B1, not imposed any particular restrictions.

Examples of methods that can be used include a method in which the reaction product obtained in stage B1, enter into interaction in the presence of acid and metal in the organic solvent, as well as the way in which hydrogen is added and enter into interaction with the reaction product obtained in stage B1, in an organic solvent.

Examples of acids used in the above method include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid, propionic acid and butane acid.

Examples of metals used in the above method include zinc, iron, tin, cobalt, Nickel and aluminum. The metal preferably is present in the form of fine powder.

In respect of the amounts used of the acid and metal, and there is no particular restrictions, provided that they are sufficient to produce the amount of hydrogen required for the implementation of reduction reaction. The required amount of hydrogen is preferably in the range from 0.6 to 1.5 moles per 1 mole of the halogenated derivative of picoline represented by the formula (14), and preferably is in the range from 1.2 to 3.0 moles per 1 mole of the halogenated derivative of picoline represented by the formula (15).

Typically, the reduction is carried out at a temperature in the range from - 20°C to the boiling point and preferably at a temperature of from 20 to 4°C.

In those cases, when performing the recovery of the reaction product, in which X represents a bromine atom, obtained using brainwashes agent as the halogenation agent at stage B1, particularly desirable is a method, which includes the interaction of the reaction product obtained in stage Bl, it is a brominated derivative of picoline represented by the formula (4), and/or brominated derivative picoline, represented by the formula (5), with a complex ester of phosphorous acid and a base in an organic solvent.

Ester of phosphorous acid used in the above method, represented by the formula P(OR)3where the oxidation state of phosphorus is equal to +3. R represents a hydrogen atom, alkyl group, aryl group or the like, and at least one of the three groups R is a group other than a hydrogen atom.

Examples of esters of phosphorous acid include triphenylphosphite, Tris(nonylphenyl)FOSFA, Tris(2,4-tert-butylphenyl)FOSFA, dinonylphenyl, tridesilon, trioctylphosphine, trioctadecyl, distearyldimethylammonium, tricyclohexylphosphine, monomethylacetylphosphite, monooksighenaza, distearyldimethylammonium, bis(2,4-di-tert-butylphenyl)pentaerythritol, bis(2,6-di-tert-butyl-4-were)PE is theatricalised, 2,2-methylene-bis(4,6-di-tert-butylphenyl)octylphosphine, dimethylphosphite, diethylphosphate, trimethylphosphite and triethylphosphite.

The amount of ester of phosphorous acid is preferably in the range from 0.1 to 20 moles per 1 mole of the brominated derivative picoline, represented by the formula (4), and preferably is in the range from 0.2 to 40 moles per 1 mole of the brominated derivative picoline, represented by the formula (5).

Examples of bases used in the above method include hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide;

hydroxides of alkaline earth metals, such as magnesium hydroxide and calcium hydroxide; carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate; hydrides such as sodium hydride and calcium hydride; alkoxides of metals such as sodium methoxide, ethoxide sodium and magnesium methoxide; and organic bases such as triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, 4-(dimethylamino)pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo[4.3.0]non-5-ene.

The amount of base is preferably in the range from 0.1 to 10 moles per 1 mole of the brominated derivative picoline, represented by the formula (4), and preferably m is carried out in the range from 0.2 to 20 moles per 1 mole of the brominated derivative picoline, represented by formula (5).

In relation to the conduct of actions, etc. taken for the reaction between the product obtained at stage B1, a complex ester of phosphorous acid and base, not imposed any particular restrictions. For example, the reaction can be carried out with a gradual addition of ester of phosphorous acid, a base and, if necessary, the phase transfer catalyst, to a solution of an organic solvent containing the reaction product obtained in stage B1. The temperature during the period of time from the beginning of the reaction until completion of the reaction can either be kept constant or can vary, but preferably the temperature is in the range from -70°C to +100°C., and more preferably in the range from -10°C to +50°C.

In relation to the organic solvent used in stage B2, not imposed any particular restrictions, and examples of such solvents include the same organic solvents that can be used on stage B1. The reaction product is not necessary to extract from the received at stage B1 of the reaction solution, and this reaction solution can simply be used at stage B2, as is.

According to the present invention stage B2 is preferably performed in the presence of a phase transfer catalyst.

P is emery of phase transfer catalysts include Quaternary ammonium salts; Quaternary phosphonium salts of such as chloride tetrabutylphosphonium, bromide tetrabutylphosphonium, chloride benzyltrimethylammonium and bromide benzyltriphenylphosphonium; and macrocyclic polyethers, such as 12-crown-4, 18-crown-6 and benzo-18-crown-6. Among these compounds, Quaternary ammonium salts are preferred.

Examples of Quaternary ammonium salts include chlorides, such as chloride of Tetramethylammonium, chloride of tetraethylammonium, chloride, Tetra-n-Propylamine, chloride designed, chloride of benzyltriethylammonium and chloride of benzyltrimethylammonium; bromides such as bromide of Tetramethylammonium, bromide of tetraethylammonium, bromide, Tetra-n-Propylamine, tetrabutylammonium bromide, bromide designed, bromide of benzyltriethylammonium and bromide of butylcarbamoyl; and iodides, such as iodide of Tetramethylammonium, iodide of tetraethylammonium, iodide, Tetra-n-Propylamine, iodide designed, iodide of benzyltriethylammonium and iodide of benzyltriethylammonium. Among these compounds, preferred is tetrabutylammonium bromide.

The amount of the phase transfer catalyst is preferably in the range from 0.001 to 10 moles and more preferably in the range from 0.01 to 1 mol per 1 mol of compound represented by formula (2). When using catalysis is ora interfacial transfer in the amount which corresponds to this range, the target product can be obtained with a good yield.

When conducting stage B2 dihalogenoalkane derived picoline, represented by the formula (14), and/or trihalomethane derived picoline, represented by the formula (15), in turn monohalogenated derived picoline, represented by the formula (3). As a result, the relative content monohalogenated derived picoline, represented by the formula (3), in the reaction system is increased and its selection becomes easy.

After performing each of the reactions of the above stages B1 and B2 can be made normal operations post-processing. After that, the target monohalogenated derived picoline, represented by the formula (3)may be selected. In addition, if you require additional cleaning product that can be applied such traditional cleaning methods as distillation, extraction, recrystallization or column chromatography.

The structure of the target product can be identified and confirmed by spectra1H-NMR, IR, mass spectra and by using elemental analysis, etc.

Halogenated derivative picoline, obtained using the method of receiving according to the present invention, can be used as about itocnode connection to receive the active ingredients of agrochemical compositions, to promote the growth of agricultural and horticultural crops, as intermediate compounds for the production of the active ingredients and substances that prevent the fouling by microorganisms, which prevent the buildup of crustaceans and molluscs as intermediate compounds for the production of the active ingredients of fungicides and as an intermediate for production of the active ingredients of antibacterial and protects from mold reagents for walls and bathrooms or for shoes and clothing.

When using the intermediate product of the present invention can inexpensively and efficiently to get the active ingredients of agricultural compositions, fungicides and antibacterial and protects from mold reagents.

3. Industrially advantageous method of deriving tetrasociological, which shows the superior antagonistic properties against plant diseases

Derived tetrasociological represented by the formula (9), according to the present invention is a new compound and is suitable as intermediate compounds for deriving tetrasociological represented by the formula (10).

The method of deriving tetrasociological represented by the formula (9), includes a step S1 of interaction halogenic the cell derived picoline, represented by the formula (7), with the derived tetraallyloxyethane represented by the formula (8).

Furthermore, the method of deriving tetrasociological represented by the formula (10), includes the above stage C1 stage and C2 processing of the reaction product obtained in stage S1, the base.

[Stage C1]

The original substance used in the method of receiving according to the present invention is a halogenated derivative of picoline represented by the formula (7).

R1Cin the formula (7) represents an unsubstituted or substituted alkyl group or unsubstituted or substituted alkoxygroup. The Deputy in R1Cthere is no particular restrictions, provided that it is inactive in the reaction with a derivative tetrasociological represented by the formula (8).

The alkyl group for R1Ccan be linear, branched or cyclic. In addition, the alkyl group preferably contains 1 to 6 carbon atoms.

Examples of unsubstituted alkyl groups include metal group, ethyl group, n-sawn group, ISO-sawn group, n-boutelou group, ISO-boutelou group, sec-boutelou group, tert-boutelou group, n-pentelow group, n-aktiline group, cyclopropyl group, cyclobutyl group, the Cyclops is a stylish group, tsiklogeksilnogo group, cycloheptyl group, 2,2-dimethylcyclopropane group and mental group.

Examples of substituted alkyl groups include chloromethylene group, formeterol group, triptorelin group, methoxymethyl group, ethoxymethyl group, methoxyamino group, methoxypropyl group, ethoxymethylene group, methoxybutyl group, methoxyamino group, propoxyethyl group, 2-methoxy-1,1-dimethylethylene group, 1-ethoxy-1-methylamino group, carbomethoxyamino group, 1-carboethoxy-2,2-dimethyl-3-cyclopropyl group, hydroxymethylene group, hydroxyethylene group and 1-hydroxypropyl group. Preferably the substituted alkyl group is halogenating group.

Alkoxygroup for R1Ccan be linear, branched or cyclic. In addition, alkoxygroup preferably contains from 1 to 6 carbon atoms.

Examples of unsubstituted alkoxygroup include a methoxy group, ethoxypropan, n-propoxylate, out-propoxylate, n-butoxypropyl, out-butoxypropyl, sec-butoxypropyl, tert-butoxypropyl, n-pentyloxy, n-hexyloxy, n-decyloxy, cyclopropylamino, cyclobutylamine, cyclopentylamine, cyclohexyloxy and methyloxirane.

Examples of substituted Alcock is igroup include chlorotoxin, formatexpr, cryptometer, methoxyethoxy, ethoxyethoxy, methoxyethoxy, 3-ethoxypropanol, 2-toxinotype, 4-butoxyethoxy, 1-butoxyethoxy, pharmacokineticist, dichloromethoxy, 1,2-dibromo-3-methoxypropane and 3 isopropoxy-2-methylpropoxy.

R2Cin the formula (7) represents an unsubstituted or substituted alkoxycarbonyl group or unsubstituted or substituted acyl group, and specific examples include the same groups as those described above for R2b.

Among the above groups, R2Cin the formula (7) preferably represents unsubstituted or substituted bataillou group.

Examples of substituted benzoline groups include 2,6-dimethoxybenzoyl group, 3,5-nitrobenzoyl group, 2,4,6-trichlorobenzoyl group and 4-chlorobenzoyloxy group.

X in the formula (7) represents a halogen atom. Examples of halogen atoms include fluorine atom, chlorine atom, bromine atom and iodine atom. From these values, it is preferable, a chlorine atom and a bromine atom.

Z in the formula (7) represents a halogen atom, a cyano, a nitro-group, a hydroxyl group, Tilney group, formyl group, carboxyl group, unsubstituted or substituted by an amino group, unsubstituted or Sames is nnow alkyl group, unsubstituted or substituted alkenylphenol group, unsubstituted or substituted alkylamino group, unsubstituted or substituted aryl group, unsubstituted or substituted heterocyclic group, OR3, S(O)pR3, COR3or CO2R3.

Examples of halogen atoms for Z include the same atoms as those described above for the halogen atom for x

Unsubstituted amino group Z is a group having a structure represented by-NH2. Examples of substituted amino groups include methylaminopropyl, dimethylaminopropyl, methylaminopropyl, diethylaminopropyl, tert-butoxycarbonylamino, tert-butoxycarbonylamino, acetylneuraminic, acetylationgrade and benzylmethylamine.

Examples of unsubstituted or substituted alkyl groups for Z include the same groups as those described above for unsubstituted or substituted alkyl group for R1C.

Unsubstituted or substituted Alchemilla group Z preferably contains 2 to 8 carbon atoms.

Examples of unsubstituted alkenyl groups include vinyl group, 1-propenyloxy group, 2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-methyl-2-propenyloxy group, 2-methyl-2-propenyloxy group, 1-pentanediol group, 2-pentanediol gr the PPU, 3-pentanediol group, 4-pentanediol group, 1-methyl-2-butenyloxy group, 2-methyl-2-butenyloxy group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group and 5-hexenyl group.

Examples of substituted alkenyl groups include 2-chloroanilino group, 2-veretenenko group, 3,3,3-Cryptor-1-pentanediol group, 1,2,2-triptorelin group, 2,3,3-Cryptor-2-propenyloxy group, 2,3,3-triiodo-2-propenyloxy group and 2-methoxyaniline group.

Unsubstituted or substituted Alchemilla group Z preferably contains 2 to 8 carbon atoms.

Examples of unsubstituted etkinlik groups include etinilnoy group, 1-propenyloxy group, 2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-methyl-2-propenyloxy group, 2-methyl-3-butenyloxy group, 1-pantanillo group, 2-pantanillo group, 3-pantanillo group, 4-pantanillo group, 1-methyl-2-butenyloxy group, 2-methyl-3-pantanillo group, 1-hexylamino group and 1,1-dimethyl-2-butenyloxy group.

Examples of substituted etkinlik groups include 2-chloroethylene group, 2-peratively group, 3-fluoro-1-propenyloxy group, 3,3,3-Cryptor-1-propenyloxy group, 3-fluoro-2-propenyloxy group and 3-iodo-2-propenyloxy group.

Unsubstituted or substituted aryl group for Z, not only is em a monocyclic or polycyclic aryl group. In polycyclic aryl group, provided that at least one ring is aromatic ring, each of the remaining ring may be saturated alicyclic ring, an unsaturated alicyclic ring or aromatic ring.

Examples of the unsubstituted aryl group include phenyl group, 1-naftalina group, 2-naftalina group, azulinebloo group, indenolol group, indenolol group and tetracyline group.

Examples of substituted aryl groups include 6-methylphenylene group, 4-methylphenyl group, 4-florfenicol group, 4-chloraniline group, 2,4-dichloraniline group, 3,4-dichloraniline group, 3,5-dichloraniline group, 2,6-differenly group, 4-trifloromethyl group, 4-metoksifenilny group, 3,4-dimethoxyphenyl group, 3,4-methylenedioxyphenyl group, 3-phenoxyphenyl group, 4-triphtalocyaninine group and 4-methoxy-1-naftalina group.

Examples of the unsubstituted heterocyclic groups for Z include unsaturated heterocyclic 5-membered ring groups such as a furan-2-ilen group, furan-3-ilen group, thiophene-2-ilen group, thiophene-3-ilen group, pyrrol-2-ilen group, pyrrol-3-ilen group, oxazol-2-ilen group, oxazol-4-ilen group, oxazol-5-ilen group, a thiazol-2-ilen group, thiazol-4-ilen group, thiazol-5-yl) - Rev. Naya group, etoxazole-3-ilen group, isooxazolyl-4-ilen group, isooxazolyl-5-ilen group, isothiazol-3-ilen group, isothiazol-4-ilen group, isothiazol-5-ilen group, imidazol-2-ilen group, imidazol-4-ilen group, imidazol-5-ilen group, a pyrazole-3-ilen group, pyrazole-4-ilen group, a pyrazole-5-ilen group, 1,3,4-oxadiazol-2-ilen group, 1,3,4-thiadiazole-2-ilen group, 1,2,3-triazole-4-ilen group, 1,2,4-triazole-3-ilen group and 1,2,4-triazole-5-ilen group; unsaturated heterocyclic 6-membered ring group, such as pyridine-2-ilen group, pyridine-3-ilen group, pyridine-4-ilen group, 5-chloro-3-Peregrina group, 3-trifluoromethyl-2-Peregrina group, pyridazin-3-ilen group, pyridazin-4-ilen group, pyrazin-2-ilen group, a pyrimidine-5-ilen group, 1,3,5-triazine-2-ilen group and 1,2,4-triazine-3-ilen group; and saturated or partially unsaturated heterocyclic groups, such as tetrahydrofuran-2-ilen group, tetrahydropyran-4-ilen group, piperidine-3-ilen group, pyrrolidin-2-ilen group, morpholinopropan, piperidinium, piperazinone, N-methylpiperazine group, aziridine group, azetidine group, pyrrolidino group and oxazoline-2-ilen group.

Examples of substituted heterocyclic groups include 3-triptorelin-2-ilen group, 4-triptoreline-2-pyridyloxy group, 3-ethyl-1-pyrazolidine group, 4-trifluoromethyl-1-imidazolidinyl group and 3,4-debtorprovidian group.

R3in OR3, S(O)pR3, COR3and CO2R3groups for Z represents an unsubstituted or substituted by an amino group, unsubstituted or substituted alkyl group, unsubstituted or substituted alkenylphenol group, unsubstituted or substituted alkylamino group, unsubstituted or substituted aryl group or unsubstituted or substituted heterocyclic group.

In addition, p represents the number of oxygen atoms in the parentheses is an integer from 0 to 2.

Examples of the unsubstituted or substituted amino, unsubstituted or substituted alkyl groups, unsubstituted or substituted alkenyl groups, unsubstituted or substituted etkinlik groups, unsubstituted or substituted aryl group or unsubstituted or substituted heterocyclic group for R3include the same groups as those described above for R1Cand Z.

Specific examples OR3include a methoxy group, ethoxypropan, n-propoxylate, out-propoxylate, n-butoxypropyl, sec-butoxypropyl, out-butoxypropyl, tert-butoxypropyl, methoxyethoxy, ethoxyethoxy, methoxyethoxy, ethoxyethoxy, vinyloxy, 1-propenyloxy, 2-propenyloxy, atenololviagrawp, 1 propenyloxy is the Rupp, 2-propenyloxy, aminochrome, methylaminopropyl, diethylaminoacetate, methoxycarbonylamino, fenoxaprop, trichlormethiazide, cryptometer, dipterocarp, 2,2,2-triptracker, pentafluoropropyl and 2 floratone group.

Specific examples S(O)pR3include dimethylaminoisopropyl, chloromethylthiazole, 3-butylthiourea, tinytip, 3-methylphenylthio, methylsulfinyl group, ethylsulfinyl group, 1-butanesulfonyl group, 1-hexanesulfonic group, 2,3-dimethylphenylimino group, methylsulfonyl group, dimethylaminomethyl group, N-ethyl-N-methylaminomethyl group, n-hexylaniline group, 2-methyl-2-butanesulfonyl group, 2-propylsulfonyl group, 2-naphthylmethyl group, phenylsulfonyl group, 2-nitrophenylacetylene group and p-tolilsulfonil group.

Specific examples COR3include acetyl group, benzoyloxy group, propanolol group, 1-propelleronline group, tert-butylcarbamoyl group, cyclopropanecarbonyl group, cyclobutanecarbonyl group, cyclopentanecarbonyl group, vinylcarbazole group, 1-propionylcarnitine group, 2-propionylcarnitine group, ISO-propionylcarnitine group, 1-PROPYNYL ebonyjoy group, 2-propionylcarnitine group, 3-butylcarbamoyl group, methylaminomethyl group, dimethylaminocarbonylmethyl group, N-methyl-N-ethylaminomethyl group, aziridinyl group, azetidinol group, pyrrolidinecarbonyl group, piperidinylcarbonyl group, morpholinomethyl group, piperazinylcarbonyl group and N-methylpiperazine group.

Specific examples of CO2R3include methoxycarbonyl group, triphtalocyaninine group, 1-interracialporno group, 2-propionylcarnitine group and phenoxycarbonyl group.

Among the above groups Z in the formula (7) preferably represents a halogen atom, unsubstituted or substituted by an amino group, unsubstituted alkyl group, OR3or SR3and more preferably represents unsubstituted or substituted by an amino group, unsubstituted alkyl group, OR3or SR3. Unsubstituted or substituted amino group Z preferably represents an unsubstituted amino group or dialkylamino, unsubstituted alkyl group preferably contains 1 to 4 carbon atoms, OR3preferably represents alkoxygroup containing 1 to 4 carbon atoms, and SR3preferably represents Alky is tigroup, containing 1 to 4 carbon atoms.

The value of m in the formula (7) shows the number of the substituents Z and an integer from 0 to 3. When m is 2 or more, the substituents Z may be the same or different from each other. Particularly preferably, when m is 0.

Halogenated derivative picoline, represented by the formula (7)can be obtained, for example, by interaction of 2-substituted derivative amino-6-methylpyridine having the corresponding structure, with a halogenation agent.

At stage S1 the substance reacting with the halogenated derivative of picoline represented by the formula (7), is a derivative of tetraallyloxyethane represented by the formula (8).

In the formula (8) Y is an unsubstituted or substituted alkyl group. Examples of unsubstituted or substituted alkyl group for Y include the same groups as described for R1C. Unsubstituted or substituted alkyl group for Y preferably represents an unsubstituted alkyl group, more preferably unsubstituted alkyl group containing 1 to 6 carbon atoms, and most preferably metal group.

In the formula (8), And represents a halogen atom, unsubstituted or substituted alkyl group, unsubstituted or substituted alkoxygroup, cyano, unsubstituted what does substituted alkylsulfonyl group, the nitro-group or unsubstituted or substituted aryl group.

Examples of halogen atoms, unsubstituted or substituted alkyl groups, unsubstituted or substituted alkoxygroup and unsubstituted or substituted aryl groups for a include the same atoms and groups as those described above for R1Cand z is Unsubstituted or substituted alkyl group And preferably represents an unsubstituted alkyl group or halogenation group, and more preferably represents an unsubstituted alkyl group containing from 1 to 6 carbon atoms, or halogenation group containing from 1 to 6 carbon atoms. Unsubstituted or substituted alkoxygroup to And preferably represents an unsubstituted alkoxygroup or halogenlampe, and more preferably represents an unsubstituted alkoxygroup containing from 1 to 6 carbon atoms, or halogenlampe containing from 1 to 6 carbon atoms.

Examples of unsubstituted alkylsulfonyl groups for a include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, ISO-propylsulfonyl group and tert-butylsulfonyl group. Examples of substituted alkylsulfonyl groups include 2-pyridylmethylamine group, 3-pyridylmethylamine group, chlorotalpa the ilen group, cyanomethylene group, 1-cyanoethylene group, 2-cyanoethylene group, micrometeorology group, chloromethanesulfonyl group, hermetically group, diplomatically group, triftormetilfullerenov group, 2-veratraldehyde group, 2,2,2-triftormetilfullerenov group, ethoxymethyleneamino group, ethoxymethyleneamino group, 1-methoxyethylamine group, 2-methoxyethylamine group and 2-chlorocarbonylsulfenyl group. Unsubstituted or substituted alkylsulfonyl group And preferably represents an unsubstituted alkylsulfonyl group, and more preferably unsubstituted alkylsulfonyl group containing from 1 to 6 carbon atoms.

In the formula (8) ncrepresents the number of substituents and is an integer from 0 to 5. When ncis 2 or more, the substituents may be identical or different from each other. Particularly preferably, when nc0.

The interaction between halogenated picoline derivative represented by the formula (7), and derived tetracyeline represented by the formula (8), at the stage S1 is a traditional reaction, which involves a combination between the group of halogen and a hydroxyl group. The reaction may be you who Olney, for example, in accordance with the method described in non-examination of the patent application Japan, first published under No. 2003-137875, or in the description of the international patent application WO 03/016303. Typically, the reaction is performed in the presence of a base.

The examples used in the reaction of bases include hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide; hydroxides of alkaline earth metals, such as magnesium hydroxide and calcium hydroxide; carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate and calcium carbonate; hydrides such as sodium hydride and calcium hydride; alkoxides of metals such as sodium methoxide, ethoxide sodium and magnesium methoxide; and organic bases such as triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, 4-(dimethylamino)pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo[4.3.0]non-5-ene. Any connection of these bases may be used individually or may be used in combination of two or more bases.

The number used at the stage S1 of the base, usually is in the range from 0.01 to 100 moles, and preferably from 0.1 to 5 moles per 1 mol of derived tetraallyloxyethane represented by the formula (8).

Interaction at the stage S1 may be about what can be found in the presence of a solvent or without using a solvent.

In respect of the used solvent, and there is no particular restrictions, provided that the solvent is not active in the reaction. Examples of solvents include solvents based on hydrocarbons, such as pentane, hexane, heptane, benzene, toluene and xylene; solvents on the basis of halogen, such as dichloromethane, chloroform and carbon tetrachloride; solvents on the basis of nitrile, such as acetonitrile and propionitrile; solvents on the basis of simple ethers such as diethyl ether, dioxane and tetrahydrofuran; solvents based on amides, such as N,N-dimethylformamide, N,N-dimethylacetamide and N-organic; solvents on the basis of sulfoxidov, such as dimethylsulfoxide; and mixed solvents of these solvents.

In relation to the conduct of actions, etc. taken for the reaction between the halogenated picoline derivative represented by the formula (7), and derived tetraallyloxyethane represented by the formula (8), there is no particular restrictions. For example, the reaction can be performed by adding the base and derived tetraallyloxyethane represented by the formula (8)to a solution of an organic solvent containing a halogenated derivative of picoline represented by the formula (7).

The temperature during the period is the time from the beginning of the reaction until completion of the reaction at the stage S1 may either be maintained constant, or to vary, but preferably the temperature is in the range from -70°C to +200°C, and more preferably in the range from -20°C to +100°C. the reaction Time varies depending on reaction scale and the like, but typically is in the range from 30 minutes to 24 hours.

In the implementation stage S1 derived tetrasociological represented by the formula (9)can be obtained industrially advantageous way. Derived tetrasociological represented by the formula (9), is a new compound and is very useful as an industrial intermediate for deriving tetrasociological represented by the formula (10)described below.

In the formula (9) R1C, R2C, Z, m, And ncand Y take the same values as defined above in the formula (7) or the formula (8).

[Stage C2]

Then at the stage S2 derived tetrasociological represented by the formula (10)can be obtained by treating the reaction product obtained in stage S1, the base.

The reaction product obtained in stage S1, namely derived tetrasociological represented by the formula (9)may be entered into interaction with the base without performing any stages of purification of the reaction solution obtained in stage S1, or, alternatively, the reaction of the races is a thief, obtained at the stage S1 may be directed at the purification step to isolate the reaction product, namely derived tetrasociological represented by the formula (9), which can then be processed by the Foundation. Examples of stages of purification include distillation, recrystallization or column chromatography.

In relation to the base used at the stage S2, and there is no particular restrictions, provided that the substrate is capable of removing groups of R2Cfrom the derived tetrasociological represented by the formula (9). Examples of bases include hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide; hydroxides of alkaline earth metals, such as magnesium hydroxide and calcium hydroxide; carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate and calcium carbonate; hydrides such as sodium hydride and calcium hydride; alkoxides of metals such as sodium methoxide, ethoxide sodium and magnesium methoxide; and organic bases such as triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, 4-(dimethylamino)pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo[4.3.0]non-5-ene. Any connection of these bases may be used individually or may be used in combination of two or the more bases.

The number used at the stage S2 of the base, usually is in the range from 0.01 to 100 moles, and preferably from 0.1 to 5 moles per 1 mole of the derivative tetrasociological represented by the formula (9). When the reaction solution obtained in stage S1, is used at the stage S2 without removal of the base, the number added at the stage of C2 can be adjusted based on the number used at the stage S1.

The reaction at the stage of C2 can be carried out in the presence or in the absence of solvent. In respect of the used solvent, and there is no particular restrictions, provided that the solvent is not active in the reaction. Specific examples of solvents include the same solvents as those described for stage S1. If the solvent used in stage C2, is the same solvent used in stage S1, there is no need to replace the solvent in the transition from stage S1 to step S2, which is an advantage in terms of cost of production.

Regarding procedures, etc. are accepted for the processing of the reaction product obtained in stage S1, the base, not imposed any particular restrictions. For example, the reaction may be carried out by adding a base to the solution of the organic solvent, containing the reaction product obtained in stage S1, namely derived tetrasociological represented by the formula (9).

The temperature during the period of time from the beginning of the reaction until completion of the reaction at the stage S2 can either be kept constant or can vary, but generally the temperature is in the range from 0°C. to the boiling point of the solvent, and preferably the temperature is in the range from 10°C to 60°C. the reaction Time varies depending on the concentration of substrate and reaction scale and the like, but typically is in the range from 5 minutes to 24 hours.

In the implementation stage C2 derived tetrasociological represented by the formula (10)can be obtained industrially advantageous method.

In the formula (10), R1C, Z, m, And ncand Y take the same values as defined above in the formula (7) or the formula (8).

After completion of the reaction stage C2 can be done with ordinary operation processing. Target derived tetrasociological represented by the formula (10)can then be isolated from the reaction mixture. In addition, in those cases requiring additional purification of the product can be applied traditional methods of purification, such as distillation, extraction, recrystallization or column chromatography.

Structure zelenogradprojekt can be identified and confirmed using spectra 1H-NMR, IR and mass spectroscopy, and by elemental analysis and the like.

Derived tetrasociological represented by the formula (10), obtained using the method of receiving according to the present invention, can be converted into a salt. Salt can be obtained in accordance with customary methods, by processing the derived tetrasociological represented by the formula (10), acid.

Derived tetrasociological represented by the formula (10)or its salt obtained using the method of receiving according to the present invention, are the ideal active ingredients of fungicides or the like. Fungicides can be used, for example, as agrochemical compositions which promote the growth of agricultural and horticultural crops, as agents that prevent the fouling by microorganisms, which prevent the buildup of crustaceans and mollusks, and as an antibacterial reagents and chemicals that prevent the formation of mold, walls and bathrooms or shoes and clothing.

Examples

The present invention is described in detail below based on a series of examples, but the present invention should not be construed as limited only given examples.

(Example A1)

10,52 g (2.5 mmol) of the compound (a) was dissolved in 1.25 ml of toluene (0.5 l/mol). A solution of the compound (a) was then added dropwise at room temperature to the liquid obtained by the addition of 0.13 g of sodium hydride (55%) (1.2 equiv.), to a mixture solvent consisting of toluene and N,N-dimethylformamide at a ratio of 4/1 (2 l/mol)and the resulting mixture is then kept at room temperature for 30 minutes.

Then 0,42 g (1.2 EQ.) of benzoyl chloride were added dropwise while cooling to the reaction mixture and the resulting mixture was stirred at the temperature for 20 minutes.

The reaction mixture was twice extracted with ethyl acetate (2 l/mol) and the extract is then washed with saturated saline (2 l/mol), dried over anhydrous magnesium sulfate, filtered and concentrated. Thus obtained crystals are then washed with chilled n-hexane (2 l/mol). Received the compound represented by formula (b) (hereinafter referred to as "compound (b), the amount of 0.66, the Output amounted to 84.6%.

(Example A2)

(Bromination)

0.31 g (1 mmol) of the compound (b) was dissolved in 4 ml of chlorobenzene (4 l/mol) and then to the resulting solution was sequentially added to 0.29 g (1 equiv.) 2,5-di-tert-butylhydroquinone and 0.03 g (0.2 equiv.) 2,2'-azobis-isobutyronitrile, followed by stirring at 90°C for one hour. Received the second liquid was then cooled to room temperature. The resulting liquid is then washed with 1N aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate, followed by removal of solvent from a liquid mixture by distillation under reduced pressure. The residue was purified column chromatography on silica gel (solvent : hexane/ethyl acetate =3/1)to give 0.15 g (yield: 38%) of the compound represented by formula (C).

Using the same procedure described for the above method, obtained compound represented by the formula (1-a), are shown in table 1, the compound represented by the formula (1-b), are shown in table 2, and the compound represented by formula (1)shown in table 3. Physical properties, etc. of the compounds shown in table 1 and table 2. In tables Measo means methoxycarbonyl group, EtOCO means ethoxycarbonyl group, AC means acetyl group and Bz means benzoyloxy group.

Table 1
No. of connectionsR1Physical propertiesNMR
a-1MeasoTPL of 57.5 and 57.6°C/td>
a-2EtOCO1H-NMR (CDCl3) δ ppm: 1,2 (t, 3H), and 1.4 (s, 9H), of 2.5 (s, 3H), 4.2 (q, 2H), 7,0 (d, 1H), and 7.1 (d, 1H), and 7.6 (t, 1H)
a-3AUTPL 77,4 is 77.5°C
a-4BzTPL 93,7-93,8°C
a-5p-NO2-BzTPL 114,8-USD 114.9°C

Table 2
No. of connectionsXpR'Physical propertiesNMR
a-6Br1MeasoTPL 82,8-82,9°C
a-7Br1EtOCOTPL 63,9-64,0°C
a-8Br1AcTPL 98,6-100,4°C
a-9Br1Bz1H-NMR (CDCl3) δ ppm: 1,3 (s, 9H), 4,4 (s, 2H), 7,29 (d, 1H). 7,34 (d, 1H), and 7.4 (d, 2H), and 7.5 (d, 1H), and 7.8 (m, 3H)
a-10Cl1Bz1H-NMR (CDCl3) 5 ppm: 1,3 (s, 9H), and 4.6 (s, 2H), and 7.3 (d, 1H), 7,45 (m,3H), and 7.5 (d, 1H), and 7.8 (m, 3H)
a-11Cl1p-NO2-BzTPL 89,5-89,6°C

Table 3
No. of connectionsR0R1(Z)m(X)n
a-12tBuOMeaso HF
a-13tBuOEtOCOHC1
a-14tBuOAcHBr
a-15tBuOBzHI
a-16tBuOp-NO2-BzHBr2
a-17MeOCH2OMeasoHH
a-18EtOC2H4CH(Me)OBzHH
a-19iPi-OS3H6AboutAcHH
a-20(MeO)2CHCH2C(Me)2OEtOCOH H
a-21MeOC2H4CH(EtO)0AcHH
a-22Measn2BzHBr2
a-23(MeO)2CH2p-NO2-BzHBr
a-24MeC(EtO)2AcHH
a-25(MeO)2CH4MeasoHH
a-26EtOCH2EtOCOHH
a-271,3-dioxane-2-thouMeasoHH
a-281,dioxan-2-iletiEtOCO HF
a-291,3-dioxane-2-ylpropylAcHCl
a-301,3-dioxane-2-libutilBzHBr
a-311,3-dioxane-2-alpentalp-NO2-BzHI
a-32MeC-NOMeMeasoHH
a-33MeONOnPrEtOCOHH
a-34EtC=NOEtAcHH
a-35nPrC-NOMeBzHH
a-36iPrC=NOMep-NO2-BzH H

(Example B1): Obtain tert-butyl benzoyl-(6-methylpyridin-2-yl)carbamate

In the reactor, purged with nitrogen, was loaded with 40 ml of N,N-dimethylformamide and then added 5,23 g of sodium hydride (purity: 55%) and 160 ml of toluene. A solution containing of 20.8 g of tert-butyl(6-methylpyridin-2-yl)carbamate in 50 ml of toluene, was added dropwise to the suspension in the reactor over a time period of 20 minutes in the temperature range from 20°C to 25°C. After completion of adding dropwise, the mixture was stirred for 30 minutes at a temperature in the range from 20°C to 25°C. Then the reaction mixture was cooled to 5°C or below and within 15 minutes was added dropwise to 13.9 ml of benzoyl chloride in the temperature range from 0 to 5°C. After completion of adding dropwise, the mixture was stirred for 10 minutes at a temperature in the range from 0 to 5°C. Then the reaction mixture was poured into 200 ml ice water and the separated organic and aqueous layers. The aqueous layer was extracted with 20 ml of toluene, and the extract was mixed with the previously separated organic layer. The resulting solution was washed twice with 50 ml water and then washed once with 50 ml saturated salt solution. The solvent was removed by distillation under reduced pressure. To the precipitate was added hexane, and the mixture was concentrated under reduced pressure. To the precipitate fill the nutrient was added 50 ml of hexane and the mixture was heated at 60°C. The mixture is then gradually cooled to 10°C and was stirred for 30 minutes at a temperature of 10°C or below. Then the mixture was filtered. The solid is washed twice with 20 ml of hexane and then dried under heating to obtain of 29.1 g (93%) of the compound represented by formula (d).

(Example B2): Obtain tert-butyl benzoyl-(6-bromomethylphenyl-2-yl)carbamate

First of 29.1 g of tert-butyl-benzoyl-(6-methylpyridin-2-yl)carbamate was dissolved in 372 ml of chlorobenzene. To the resulting solution was added to 7.8 g of sodium bicarbonate. Then the resulting mixture was heated to 90°C., and then thereto was added 3.1 g of azobis-isobutyronitrile, followed by the addition of 26.6 g of 1,3-dibromo-5,5-dimethylhydantoin 10 portions within 80 minutes. After complete addition, the mixture was stirred at 90°C for 30 minutes. The reaction mixture was cooled to room temperature, washed with 140 ml of 1N sodium hydroxide and then washed with a mixed solution consisting of 70 ml of water and 23 ml of saturated salt solution.

Thus obtained organic layer was cooled at 5°C or below and then added separately 14.9 g of 50% sodium hydroxide, 12.0 ml of diethyl ether phosphoric acid and 1.5 g of tetrabutylammonium when the reaction was completed according to TLC. After completion of the additions, the mixture was stirred techenie minutes at a temperature in the range from 0°C to 5°C.

The disappearance of the spots corresponding to dibromoethylene and tribromoethanol, and obtaining the compounds represented by formula (e) (monobromobimane), was confirmed using thin layer chromatography. The reaction solution was used directly in example B3 without directions on further processing.

(Example B3): Obtain tert-butyl benzoyl-{6-([Z]-(1-methyl-1H-5-tetrazolyl)phenylmethanesulfonyl)-2-pyridyl}carbamate

To the reaction solution obtained in example B2 was added to 37.2 g of 20% sodium hydroxide solution and the resulting mixture was stirred for 30 minutes at a temperature in the range from 20°C to 25°C. Then was added to 18.9 g (1-methyl-1H-5-tetrazolyl)phenylmethoxy and the reaction mixture was stirred for 3.5 hours at a temperature in the range from 20°C to 25°C.

The disappearance of the target substance and obtaining the compounds represented by formula (f), was confirmed using thin layer chromatography. The reaction solution is directly used in example B4 without any further processing.

(Example B4): Obtain tert-butyl {6-([Z]-(1-methyl-1H-5-tetrazolyl)phenylmethanesulfonyl)-2-pyridyl}carbamate

To the reaction solution obtained in example B3 was added to 37.2 g of 20% sodium hydroxide solution poluchennuyu the mixture was stirred at 40°C. for 15 hours. The disappearance of the starting compounds and obtain the desired product was confirmed by thin layer chromatography. Then the reaction mixture was separated into organic and aqueous layers. Organic layer was washed 93 ml of 1N sodium hydroxide. The aqueous layer was extracted with 23 ml of chlorobenzene and the extract was mixed with the previously separated organic layer followed by washing the mixture of 47 ml of a saturated salt solution. The solvent was removed by distillation under reduced pressure, and then to the precipitate was added methanol, followed by concentrating the mixture under reduced pressure. The process of adding methanol and execution concentration under reduced pressure was further repeated twice. Then to the resulting mixture was added 47 ml of methanol and the mixture was heated under reflux to obtain a homogeneous solution. The solution is then gradually cooled to 10°C and was stirred for 30 minutes at a temperature of 10°C or below. The resulting liquid is then filtered. The solid was rinsed twice in 19 ml of methanol and then dried under heating, getting to 26.6 g of compound represented by formula (g). The melting point of the solid substance was 141,5 to 141,6°C. the Output is directly from tert-butyl benzoyl-{6-methylpyridin-2-yl}carbamate (example B2) was 70%.

(Example B5): Obtain tert-butyl and ethyl-(6-methylpyridin-2-yl)carbamate

Exactly the same method of obtaining of example B1 was used, to obtain a compound represented by the formula (h), except for the use of acetylchloride instead of benzoyl chloride. The melting point of the compound was 77,4 is 77.5°C.

(Example B6): Obtain tert-butyl acetyl-(6-bromomethylphenyl-2-yl)carbamate

First was dissolved 1,05 g (4.2 mmol) of tert-butyl-acetyl-(6-methylpyridin-2-yl)carbamate in 17 ml of chlorobenzene (4 l/mol). To the resulting solution was added 1.2 g (1 equiv.) 1,3-dibromo-5,5-dimethylhydantoin and 0.14 g (20 mol.%) 2,2'-azobis-isobutyronitrile and the resulting mixture was stirred at 90°C for one hour. Then the reaction mixture was cooled, the precipitate was removed by filtration and the filtrate was concentrated to approximately half volume.

To the thus obtained precipitate was added upon cooling of 0.58 g of the diethyl ester of phosphorous acid and 0.54 g of diisopropylethylamine and the resulting mixture was stirred at room temperature for 19 hours. The disappearance of the starting compounds was confirmed by thin layer chromatography (ethyl acetate : hexane =1:4 (volume ratio)) and then the resulting mixture was extracted with chloroform three times. The extract was dried over anhydrous magnesium sulfate and was filtered, and the solvent was then removed distillery reduced pressure.

(Example B7): Obtain tert-butyl {6-([Z]-(1-methyl-1H-5-tetrazolyl)phenylmethanesulfonyl)-2-pyridyl}carbamate

First was dissolved 0,85 g (1-methyl-1H-5-tetrazolyl)phenylmethoxy in 6 ml of chlorobenzene (1.5 l/mol). To the resulting solution at 0°C was added dropwise a 1.75 ml (2 equiv.) 20% aqueous sodium hydroxide solution, 0.27 g (20 mol.%) of tetrabutylammonium bromide and a solution obtained by dissolving the precipitate obtained in example B6, 3 ml of chlorobenzene (0.8 l/mol). The resulting mixture was stirred over night at room temperature. After confirming disappearance of the starting compounds using thin layer chromatography (ethyl acetate : hexane =1:4), the reaction mixture three times were extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was then removed by distillation under reduced pressure. The residue was purified using automated collector fractions (produced by Yamazen Corporation)to give tert-butyl acetyl-{6-([Z]-(1-methyl-1H-5-tetrazolyl)phenylmethanesulfonyl)-2-pyridyl}carbamate, with the release of 67.4%.

Then 1.28 g (2,835 mmol) thus obtained tert-butyl acetyl-{6-([Z]-(1-methyl-1H-5-tetrazolyl)phenylmethanesulfonyl)-2-pyridyl} carbamate

was dissolved in 23 ml of methanol (8 l/mol). To the resulting solution was added 3,51 ml (3 equiv.) 10% is the same sodium hydroxide solution and the resulting mixture was stirred at room temperature for 15 hours. Then the reaction liquid was concentrated. The obtained concentrate was washed with water, washed with hexane and then washed with a small amount of methanol. The product is then dried in the air, getting 0,98 g of target compound (yield: 84,5%). Output directly from tert-butyl acetyl-(6-methylpyridin-2-yl)carbamate (example B6) was 73.8%.

(Example B8): Obtain tert-butyl tert-butoxycarbonyl-(6-methylpyridin-2-yl)carbamate

First, 38 g of 6-methylpyridin-2-ylamine, 169 g of bis(tert-butoxycarbonyl)oxide, 18 ml (2,48 g) of triethylamine and 18 ml (1.84 g) of pyridine were dissolved in 340 ml of dimethylformamide. The resulting solution was then gradually heated. The temperature of the fluid in the end raised to 90°C by monitoring the status of generated carbon dioxide. The reaction mixture is then kept at this temperature for 5 hours. After confirming disappearance of the starting compounds using thin layer chromatography, the reaction mixture was poured into a mixed solution containing 500 ml of a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and the resulting mixture was then extracted with ethyl acetate. The extract is then dried over anhydrous magnesium sulfate, filtered and concentrated. Then perform the cleanup on l the responsibility column, getting 81 g (74.7 per cent) of the target product.

(Example B9): Getting 2-bis-(tert-butoxycarbonyl)amino-6-pommerellen

To 102,8 g (334 mmol) of tert-butyl tert-butoxycarbonyl-(6-methylpyridin-2-yl)carbamate was added 10,95 g (20 mol.%) 2,2'-azo-bis-isobutyronitrile and 1,330 ml of chlorobenzene. To the mixture was added 95.31 per g of 1,3-dibromo-5,5-dimethylhydantoin and then the temperature of the mixture was raised to 90°C at a speed of 2°C./minute and maintained at this temperature for one hour. Then the reaction mixture was cooled to 20°C, the precipitate was filtered and the volume of chlorobenzene was reduced to half by distillation. Thus obtained residue was cooled to 10°C or below and then add to it 46,03 g (43 ml) diisopropylethylamine and 43,08 g (58 ml) diethyl ester of phosphorous acid, followed by keeping the mixture at room temperature for 16.5 hours. After confirming disappearance of the starting compounds using thin layer chromatography, the reaction mixture was washed with 300 ml of 3N hydrochloric acid, and then further washed with 500 ml saturated salt solution. The resulting solution was then dried over anhydrous magnesium sulfate and was filtered, receiving 2-bis-(tert-butoxycarbonyl)amino-6-bromomethylphenyl.

(Example 10): Obtain tert-butyl{6-([2]-(1-methyl-1H-5-tetrazolyl)phenylmethylene oxymethyl)-2-pyridyl}carbamate

To a solution of 2-bis-(tert-butoxycarbonyl)amino-6-pommerellen obtained in example B9, added 67,7 g (1-methyl-1H-5-tetrazolyl)phenylmethoxy, 667 ml of 1N aqueous sodium hydroxide solution and 5.4 g (5 mol.%) of tetrabutylammonium bromide, and the resulting mixture was stirred at room temperature for two hours. After confirming disappearance of the starting compounds using thin layer chromatography was added 500 ml of water and 500 ml of chloroform and performed the extraction. The aqueous layer was extracted with 500 ml of chloroform and then washed with 500 ml of water. The extract was dried over anhydrous magnesium sulfate, filtered and then concentrated. Thus obtained precipitate was dissolved in 2.5 l of methanol and then added to the solution at room temperature, 1 l of 1N aqueous sodium hydroxide solution. The reaction was carried out at room temperature for about 20 hours.

Precipitated crystals were collected by filtration. Thus obtained crystals were washed three times with 500 ml of water and then dried in a desiccator, getting 98,16 g of Z-isomer of the desired product (purity: 98.5%with a yield of 72.6%). On the other hand, to the above filtrate was added to 5 l of water and the mixture was extracted three times with 1000 ml of ethyl acetate. The ethyl acetate layer was washed 1 l oxen, dried over anhydrous magnesium sulfate, filtered and then to what was centriole. Thus obtained residue was purified by use of the collected fractions produced Biotage AB, receiving of 6.1 g of the target product (E:Z isomer mixture). The total yield amounted to 77.1 percent.

(Example C1)

To 54,7 g of the solution obtained by dissolving by 5.87 g (15 mmol) of the compound represented by formula (n)in 44 ml of chlorobenzene, was added to 48.0 g (60 mmol) of an aqueous solution of NaOH with a concentration of 5 wt.%, 0.24 g (0.75 mmol) of tetrabutylammonium bromide and 3.77 g (purity: 97,0 wt.%, 18 mmol) of the compound represented by formula (o).

The resulting mixture was stirred at room temperature for 4 hours, and disappearance of the compounds represented by formula (n), and obtaining the compound represented by formula (p), confirmed by high performance liquid chromatography.

The reaction mixture was heated to 40°C. and added the 4.29 g (30 mmol) of an aqueous solution of NaOH having a concentration of 28 wt.%. The mixture was stirred at 40°C for 2.5 hours. Then the mixture was left to settle overnight and then stirred at 40°C. for 3.5 hours. The reaction mixture was divided and thus obtained organic phase was washed sequentially with an aqueous solution of NaOH with a concentration of 1 mol/l and water. After washing the organic phase was concentrated using an evaporator and the resulting precipitate bicrystalline ivali from methanol, getting between 6.08 g (of 14.8 mmol, yield: 99%) of white crystals.

The obtained white crystals were characterized by the same physical properties as the compound designated as compound number (3)-8 in table 3 WO 03/016303. It was confirmed that the obtained white crystals were compound represented by the formula (q).

(Example C2)

First of 0.47 g (1.28 mmol) of the compound represented by formula (n), was dissolved in 5 ml of acetonitrile and then added 0.2 g (1.4 mmol) of potassium carbonate. Then added 0.3 g (1.4 mmol) of the compound represented by formula (o), and the mixture was stirred at room temperature for 30 minutes. Then the mixture was left to stand overnight. Next, the reaction mixture was filtered and then concentrated under reduced pressure. Thus obtained residue was purified column chromatography, receiving 300 mg (of 0.58 mmol, yield: 46%) of white crystals. The results of NMR measurements for the thus obtained white crystals below.

1H-NMR (CDCl3, δ ppm): 1,25 (s, 9H), a 3.87 (s, 3H), and 5.30 (s, 2H), 7,21 to 7,81 (m, 13H).

It was confirmed that the obtained white crystals were compound represented by the formula (R).

(Example C3)

Except for the replacement of the compounds represented by formula (n) 2-(tert-butoxycarbonyloxyimino)-6-promoterdriven same method, as in example C2, gave compound represented by the formula (r). The results of registration NMR spectrum for the compound represented by formula (g)below.

1H-NMR (CDCl3, 5 ppm): of 1.41 (s, 9H), of 3.77 (s, 3H), 3,79 (s, 3H), 5,38 (s, 2H), 7,18 (d, 1H), 7,26 (d, 1H), 7,37 (m, 2H), 7,45 (m, 1H), 7,51 (m, 1H), 7,78 (t, 1H).

Industrial applicability

The compound containing a pyridine ring, according to the present invention can be synthesized industrially advantageous method and used as intermediate compounds for obtaining exhibiting fungicidal activity of derivatives tetrasociological. In addition, the method according to the present invention allows high selectivity and high yield 2-substituted derivatives of amino-6-halogenopyrimidines and enables industrial best way to get derivatives tetrasociological exhibiting excellent antagonistic properties against plant diseases.

1. The compound containing a pyridine ring represented by the formula (1):
,
where R0represents a C1-6alkoxygroup, C1-6alkoxy-C1-6alkoxygroup, C1-6alkoxy-C1-6alkyl group, 1,3-dioxane-2-yl-C1-6alkyl group or a group CR01C(=NOR02) (where each of R01and R02n is dependent represents a C 1-6alkyl group),
R1represents a C1-2alkoxycarbonyl group, acetyl group or benzoyloxy group which may be substituted by a nitro-group,
X represents a halogen atom, and
n represents the number of substituents X and is an integer from 0 to 3, and when n is 2 or more, the substituents X may be the same or different from each other.

2. A method of obtaining a halogenated derivative of picoline represented by the formula (3),

where R1brepresents unsubstituted alkoxycarbonyl group, and
R2brepresents unsubstituted alkoxycarbonyl group, acetyl group or benzoyloxy group which may be substituted by a nitro-group,
X represents a halogen atom,
contains: stage B1, in which the compound represented by formula (2), and halogenation agent react in an organic solvent; and phase B2, which restores the reaction product obtained in stage B1,
,
where R1band R2bin the formula (2) are the same as defined above.

3. A method of obtaining a halogenated derivative of picoline according to claim 2, in which stage B1 is performed in the presence of a base.

4. A method of obtaining a halogenated derivative picol is to claim 2 or 3, in which the organic solvent at the stage B1 is a benzene or halogenated hydrocarbons.

5. A method of obtaining a halogenated derivative of picoline according to claim 2 or 3, in which stage B2 is performed in the presence of a phase transfer catalyst.

6. A method of obtaining a halogenated derivative of picoline according to claim 2 or 3, wherein the halogenation agent is pomeroyi agent, and X represents a bromine atom.

7. The way to obtain the brominated derivative picoline, represented by the formula (6), including the interaction of the brominated derivative picoline, represented by the formula (4) and/or formula (5), a complex ester of phosphorous acid and a base in an organic solvent,
,
where R1brepresents unsubstituted alkoxycarbonyl group, and
R2brepresents unsubstituted alkoxycarbonyl group, acetyl group or benzoyloxy group which may be substituted by a nitro-group.

8. The method of deriving tetrasociological represented by the formula (10), including the state S1, in which the halogenated derivative picoline, represented by the formula (7), is reacted with a derivative tetraallyloxyethane represented by the formula (8), to obtain the derived tetrasociological, is expressed by formula (9); and the stage S2, which is derived tetrasociological represented by the formula (9) and obtained at the stage S1, is treated with a base,

where in the formula (7) R1Crepresents an unsubstituted alkyl group or an unsubstituted alkoxygroup,
R2Crepresents unsubstituted alkoxycarbonyl group or unsubstituted acyl group, and
X represents a halogen atom, and
in the formula (8) Y is an unsubstituted alkyl group.

9. Derived tetrasociological represented by the formula (9)

where R1Crepresents an unsubstituted alkyl group or an unsubstituted alkoxygroup,
R2Crepresents unsubstituted alkoxycarbonyl group or unsubstituted acyl group, and
Y is an unsubstituted alkyl group.

10. The method of deriving tetrasociological represented by the formula (9), including the state C1 at which the halogenated derivative picoline, represented by the formula (7), is reacted with a derivative tetraallyloxyethane represented by the formula (8)

where R1Crepresents an unsubstituted alkyl group or an unsubstituted alkoxygroup,
R2Crepresents unsubstituted alkoxycarbonyl the Yu group or unsubstituted acyl group,
X represents a halogen atom, and
Y is an unsubstituted alkyl group.



 

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19 cl, 29 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel compounds of formula I: or salts thereof, where: A1 denotes hydrogen, CN, CI, F, Br, OMe, (1-4C alkyl) or cyclopropyl; A2 denotes hydrogen, Cl, Br, F, (1-4C alkyl) or cyclopropyl; W denotes -C(=O)NR1- or -NR2C(=O)-; each of R1 and R2 denotes hydrogen or methyl; L denotes a chemical bond, -(CR3R4)n-(CRaRb)m-(CR5R6)-*, (2-4C)alkenylene, -O(1-4C alkyl)-*, -(1-4C alkyl)-O-*, -(1-4C alkyl)-S-*, (3-6C)cycloalkylene or hetCyc1, where the symbol "*" indicates the binding position of G, under the condition that if W denotes -C(=O)NR2-, then L is not -(CH=CH)-; m equals 0, 1 or 2; n equals 0 or 1; Ra and Rb are independently selected from hydrogen and (1-4C alkyl); R3 denotes hydrogen, (1-4C alkyl) or CH2OH; R4 denotes hydrogen or methyl; R5 denotes hydrogen, (1-4C alkyl), OH, -O(1-4C alkyl) or F; R6 denotes hydrogen, F or methyl; or R5 and R6 together with the carbon atom with which they are bonded form a cyclopropyl ring, hetCyc1 denotes a group of formula where t equals 1 or 2 and p equals 0 or 1, and the symbol "*" indicates the position of binding with G; G denotes Ar1, Ar2, naphthyl, benzo-condensed (5-6C)cycloalkyl ring, optionally substituted with one or more substitutes independently selected from Cl and OMe, benzo-condensed 5-6-member heterocyclic ring with 1-2 heteroatoms independently selected from O and N, (3-6C)cycloalkyl ring, optionally substituted with one or more substitutes independently selected from (1-4C)alkyl, oxaspirononanyl ring or t-butyl; Ar1 denotes phenyl, optionally substituted with one or more substitutes independently selected from F, Cl, Br, CF3, (1-4C)alkyl, OH, -O(1-4C alkyl), -S(1-3C alkyl), -SCF3, cyclopropyl, -CH2N(1-3C alkyl)2, -O-(2-3C)fluoroalkyl, -O-(1-3C)difluoroalkyl-O-(1-3C)trifluoroalkyl, -OCH2(cyclopropyl) and (3-4C)alkynyl; Ar2 denotes phenyl, substituted with Ar3, -O-Ar4, hetAr1 or -O-hetAr2, where Ar2 is further optionally substituted with one or more substitutes independently selected from F, O or CF3; Ar3 denotes phenyl, optionally substituted with one or more substitutes independently selected from F, CI, Br and (1-4C alkyl); Ar4 denotes phenyl, optionally substituted with one or more substitutes independently selected from F, CI, Br and (1-4C alkyl); hetAr1 denotes a 6-member heteroaryl with 1-2 nitrogen atoms, optionally substituted with one or more substitutes independently selected from (1-4C alkyl); hetAr2 denotes a 6-member heteroaryl with 1-2 nitrogen atoms, optionally substituted with one or more substitutes independently selected from (1-4C alkyl) and CF3; R7a, R7 and R8 each independently denotes hydrogen or methyl; R9 denotes hydrogen, methyl, fluorine or NO2; and R10 denotes hydrogen, methyl or fluorine; where A1, A2, W, L, G, R7a, R7b, R8, R9 and R10 assume values given in the description, which are DP2 receptor modulators which are effective in treating immunological diseases.

EFFECT: inventions relate to a method of producing compounds of formula 1, a pharmaceutical composition based on said compounds and a method of treatment.

30 cl, 1 tbl, 239 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel quinazolina derivatives, which have benzofurane substituent of formula: in which each of R1, R2, R5, R8, R9 and R10 represent H, R3 and R4 similarly represent alkoxy or methoxyethoxy group; R6 represents alkyl; R7 represents-C(O)NRaRb, and each of Ra and Rb independently represents H, alkyl, ethyl, substituted with diethylaminogroup, C3-C6cycloalkyl, or Ra and Rb together form cycloalkyl; Z represents N; X represents O, S or NR, where R represents H or alkyl.

EFFECT: invention relates to pharmaceutical composition, inhibiting KDR, based on said compounds, method of treating associated with angiogenesis disorder, representing cancer, age-related macular degeneration or chronic inflammatory disease, and method of inhibiting activity of growth factor of vessel endothelium.

18 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted pyrrolidine-2-carboxamides of formula I or their pharmaceutically acceptable salts, where values X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are given in item 1 of the formula. Compounds can be used in pharmaceutical composition, inhibiting interaction of MDM2-p53.

EFFECT: compounds can be used as anti-cancer medications.

46 cl, 4 dwg, 347 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel acyl thiourea derivatives of formula or a pharmaceutically acceptable salt thereo, where R1 is a hydrogen atom or a C1-3 alkyl group; R2 is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C6-14 aromatic hydrocarbon group or an optionally substituted saturated or unsaturated 5-7-member heterocyclic group containing 1 or 2 nitrogen or sulphur atoms, or R1 and R2, together with the nitrogen atom which they are bonded, can form an optionally substituted nitrogen-containing saturated heterocyclic group selected from a group comprising pyrrolinyl, piperidinyl, piperazinyl or morpholino group; where the substitute is selected from a group comprising a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-6 alkanoyl group, a C1-6 alkyl group, a C3-10 cycloalkyl group, a C2-6 alkenyl group, C1-6 alkoxy group, an amino group, a C1-6 alkylamino group, a C1-6 alkanoylamino group, a C1-6 alkylaminocarbonyl group, a C1-6 alkylsulphonyl group, a C6-14 aromatic group, a saturated or unsaturated 5-7-member heterocyclic group containing 1-4 nitrogen and/or oxygen atoms, a saturated or unsaturated 5-7-member heterocycyl-carbonyl group containing 1 or 2 nitrogen and/or oxygen atoms, and an oxo group; R3 is a C1-6 alkyl group; and R4 is a halogen atom; R5 and R6, which can be identical or different from each other, denote a hydrogen atom, a halogen atom, a C1-3 alkyl group which can be substituted with a halogen atom, or a C1-6 alkoxy group. The invention also relates to a pharmaceutical or anti-tumour agent based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel acetyl thiourea derivatives having c-Met inhibiting activity are obtained.

11 cl, 2 dwg, 4 tbl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (1) or salts thereof, where in formula (1) R1 is a lower C1-C6alkyl group, a lower C3-C6cycloalkyl group, a phenyl group, a heterocyclic group, which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom and a sulphur atom, or a phenyl(C1-C6alkyl) group; in cases when R1 is a lower C1-C6alkyl group, that lower C1-C6alkyl group can have, as substitute(s), one, two or three groups selected from a halogen atom, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one or two heteroatoms in the ring, selected from a nitrogen atom and an oxygen atom, a carboxyl group, a lower C1-C6alkoxycarbonyl group, a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a phenyl group; in cases when R1 is a phenyl group, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom or a sulphur atom, or a phenyl(C1-C6alkyl) group, that phenyl, heterocyclic or phenyl(C1-C6alkyl) group can contain, as substitute(s), one, two or three groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group or a lower C1-C6alkoxy group; R2 is a hydrogen atom or a lower C1-C6alkyl group; R3 is a hydrogen atom or a lower C1-C6alkyl group; R4 and R5 can be identical or different and are a hydrogen atom or a lower C1-C6alkyl group; R6 is a hydrogen atom or a lower C1-C6alkyl group; R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom; in cases where R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom, that phenyl or heterocyclic group can contain, as substitute(s), one or two groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group, a lower C1-C6alkoxy group and a nitro group; W is an oxygen atom or NR8; R8 is a hydrogen atom or a lower C1-C6alkyl group; X is an oxygen atom or a sulphur atom; Y is a lower C1-C6alkylene group; Z is an oxygen atom, a sulphur atom, NR9 or OCO; R9 is a hydrogen atom or a lower C1-C6alkyl group. The invention also relates to a pharmaceutical composition based on said compounds, having GR binding activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine as glucocorticoid receptor modulators.

10 cl, 1 tbl, 3 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining activated ester of formula (I): where R stands for C1-C6 alkyl, linear or branched, 6-membered heteroaryl with one nitrogen atom as heteroatom; Alk stands for C1-C6 alkyl, linear or branched, consisting in interaction of dicyclohexylamine salt P1 and disuccinimidylcarbonate (DSC) in solvent which represents ketone, in which salt of dicyclohexylamine and N-hydroxycuccinimide P2 precipitates.

EFFECT: method makes it possible to obtain target product with high output and good degree of purity.

10 cl, 1 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted pyrrolidine-2-carboxamides of formula I or their pharmaceutically acceptable salts, where values X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are given in item 1 of the formula. Compounds can be used in pharmaceutical composition, inhibiting interaction of MDM2-p53.

EFFECT: compounds can be used as anti-cancer medications.

46 cl, 4 dwg, 347 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

FIELD: agriculture.

SUBSTANCE: agent for control of plant diseases comprises: at least one compound chosen from tetrazolyl oxime derivatives represented by the formula , and their salts: in the formula (I) X is C1-6-alkyl group, C1-6-alkoxy group, halogen atom, nitro group, cyano group, C6-10-aryl group or C1-6-alkyl-sulfonyl group; n is an integer from 0 to 5; Y is C1-6 alkyl group; Z is a hydrogen atom, an amino group or a group represented by the formula NHC(-O)-Q; Q is a hydrogen atom, C1-8-alkyl group, C1-6-haloalkyl group, C3-6-cycloalkyl group, C1-8-alkoxy group, C3-6-cycloalkoxy group, C7-20-aralkoxy group, C1-4-alkylthio-C1-8 alkyl group, C1-4-alkoxy-C1-2-alkyl group, C1-4-acylamino-C1-6-alkyl group, C1-4-acylamino-C1-6-alkoxy group, C1-8-alkylamino group, C2-6-alkenyl group, C7-20-aralkyl group or C6-10-aryl group; R is an halogen atom; m is an integer from 0 to 3; and at least one compound selected from the group consisting of triflumizole, hydroxyisoxazole, acetamiprid and their salts.

EFFECT: invention enables to improve the efficiency of disease control.

2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel acyl thiourea derivatives of formula or a pharmaceutically acceptable salt thereo, where R1 is a hydrogen atom or a C1-3 alkyl group; R2 is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C6-14 aromatic hydrocarbon group or an optionally substituted saturated or unsaturated 5-7-member heterocyclic group containing 1 or 2 nitrogen or sulphur atoms, or R1 and R2, together with the nitrogen atom which they are bonded, can form an optionally substituted nitrogen-containing saturated heterocyclic group selected from a group comprising pyrrolinyl, piperidinyl, piperazinyl or morpholino group; where the substitute is selected from a group comprising a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-6 alkanoyl group, a C1-6 alkyl group, a C3-10 cycloalkyl group, a C2-6 alkenyl group, C1-6 alkoxy group, an amino group, a C1-6 alkylamino group, a C1-6 alkanoylamino group, a C1-6 alkylaminocarbonyl group, a C1-6 alkylsulphonyl group, a C6-14 aromatic group, a saturated or unsaturated 5-7-member heterocyclic group containing 1-4 nitrogen and/or oxygen atoms, a saturated or unsaturated 5-7-member heterocycyl-carbonyl group containing 1 or 2 nitrogen and/or oxygen atoms, and an oxo group; R3 is a C1-6 alkyl group; and R4 is a halogen atom; R5 and R6, which can be identical or different from each other, denote a hydrogen atom, a halogen atom, a C1-3 alkyl group which can be substituted with a halogen atom, or a C1-6 alkoxy group. The invention also relates to a pharmaceutical or anti-tumour agent based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel acetyl thiourea derivatives having c-Met inhibiting activity are obtained.

11 cl, 2 dwg, 4 tbl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to compounds of formula or a pharmaceutically acceptable salt of such a compound, where - X is a carbon atom and R1a and R2a together form a bond; or - X is a carbon atom, R1a and R2a together form a bond, and R1 and R2 together form a moiety , where the asterisk shows the bonding site of R2; or - X is a carbon atom, R1a is hydrogen or (C1-4)alkoxy, and R2a is hydrogen; and R1 and R2, unless indicated otherwise, independently denote hydrogen; (C1-5)alkyl; aryl, where aryl denotes naphthyl or phenyl, where said aryl is unsubstituted or independently mono- or disubstituted, where the substitutes are independently selected from a group consisting of (C1-4)alkyl, (C1-4) alkoxy and halogen; or heteroaryl, selected from pyridyl, thienyl, oxazolyl or thiazolyl, where said heteroaryl is unsubstituted; under the condition that if R2 is aryl or heteroaryl, R1 cannot be aryl or heteroaryl, where the aryl and heteroaryl are independently unsubstituted or substituted as defined above; R3 is hydrogen or -CO-R31; R31 is (C1-5)alkyl, (C1-3)fluoroalkyl or (C3-6)cycloalkyl; n equals 1, 2, 3 or 4; B is a -(CH2)m- group, where m equals an integer from 1 to 3; A is-(CH2)P-, where p equals 2 or 3; R4 is (C1-5)alkyl; W is , where R5 is hydrogen or (C1-5)alkyl; R8, R9 and R10 is independently hydrogen, halogen, (C1-5)alkyl, hydroxy, -(C1-5)alkoxy, -O-CO-(C1-5)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, -CO-(C1-5)alkoxy, (C1-2)alkoxy-(C1-4)alkoxy or -NH-CO-(C1-5)alkyl. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel compounds which are useful as calcium channel blockers are obtained.

11 cl, 2 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel indole derivatives containing a carbamoyl group, a ureide group and a substituted oxy group or to pharmaceutically acceptable salts, having general formula

,

where values of R1-R3, m are given in claim 1.

EFFECT: compounds exhibit inhibiting activity on IKKβ, which enables use thereof as a preventive or therapeutic agent for treating several diseases associated with IKKβ.

25 cl, 1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a dual action compound which is characterised by general formula [((S)-N-valeryl-N-{[2'-(lH-tetrazol-5-yl)biphenyl-4-uyl]methyl}valine) ethyl ether (2R,4S)-5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoic acid]Na1-3·xH2O, in solid form, where x equals 0-3, which is an angiotensin receptor inhibitor and a NEP inhibitor, and can be used to treat hypertension.

EFFECT: high efficiency of using the compound.

19 cl, 4 ex

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