Isoxazoline derivative and herbicide comprising its as active component

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

 

The level of technology

1. The technical field.

The present invention relates to a new derived isoxazoline and herbicide containing the derived isoxazoline as the active ingredient.

2. Description of the prior art.

Herbicide activity derived isoxazoline described, for example, in the publications of JP-A-8-22558, JP-A-9-328477 and JP-A-328483. However, the connection of the present invention, described in more detail below, are not represented in these publications.

It is desirable that the herbicides applied on useful crops, (a) could be applied to soil or foliage, (b) demonstrated sufficient herbicide action when low quantities of ingredient and (b) had a high selectivity to crops and weeds. From this point of view, the compounds described in the above publications are not fully satisfactory.

The invention

Considering the situation above, the applicants of the present invention studied herbicide effect and selectivity to crops and weeds of various compounds. In the applicants invention have found that the new derived isoxazoline has excellent herbicide action and excellent selectivity to crops and weeds. The specified discovery led to the present invention.

The present invention before aget following.

(1) Derived isoxazoline represented by the following General formula [I]or its pharmaceutically acceptable salt

where

R1and R2may be the same or different and each represents a hydrogen atom, C1-C10-alkyl group, C3-C8-cycloalkyl group or C3-C8-cycloalkyl-C1-C3-alkyl group, or the substituents R1and R2can be connected to each other to form C3-C7-spironola together with the carbon atoms to which they are linked;

R3and R4may be the same or different and each represents a hydrogen atom, C1-C10-alkyl group or C3-C8-cycloalkyl group; or the substituents R3and R4can be connected to each other to form C3-C7-spironola together with the carbon atoms to which they are linked; or the substituents R1, R2, R3or R4can form a 5-8-membered ring together with carbon atoms to which they are linked;

R5and R6may be the same or different and each represents a hydrogen atom or C1-C10-alkyl group;

Y is a 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group containing one or more heteroatoms selected from the ATO is and nitrogen, of oxygen atom and sulfur atom, and the heterocyclic group may be substituted by 0 to 6 identical or different groups selected from the following group of substituents α; when the heterocyclic group is substituted in two adjacent positions by two alkyl groups, two alkoxygroup, alkyl group and alkoxygroup, alkyl group and alkylthiol, alkyl group and alkylsulfonyl group, alkyl group and monoalkylamines, or alkyl group and dialkylamino, all of which are selected from the group of substituents α, two groups can form together with the atoms to which they are linked, 5-8-membered ring, which may be substituted by 1-4 halogen atoms; heteroatom of the heterocyclic group, when it represents a nitrogen atom may be oxidized to N-oxide;

n takes on integer values from 0 to 2.

[Group Vice α]

Hydroxyl group; Tolna group; halogen atoms; C1-C10-alkyl groups; C1-C10-alkyl groups, each of which monogamist group selected from the following group of substituents β; C1-C4-halogenoalkane group; C3-C8-cycloalkyl group; C1-C10-alkoxygroup; C1-C10-alkoxygroup, each of which monogamist group selected from the following group of substituents γ; C1-C4-halogenlampe; C3-C8-cycloalkanes; C3-the 8-cycloalkyl-C1-C3-alkoxygroup; C1-C10-allylthiourea; C1-C10-allylthiourea, each of which monogamist group selected from the following group of substituents γ; C1-C4-halogenation; C2-C6-alkeline group; C2-C6-alkenylacyl; C2-C6-alkyline group; C2-C6-alkyloxy; C1-C10-alkylsulfonyl group; C1-C10-alkylsulfonyl groups, each of which monogamist group selected from the following group of substituents γ; C1-C10-alkylsulfonyl group; C1-C10-alkylsulfonyl groups, each of which monogamist group selected from the following group of substituents γ; C1-C4-galogenzameshchennye group; C1-C10-alkylsulphonate, each of which monogamist group selected from the following group of substituents γ; C1-C4-galogenzameshchennye group; C1-C10-alkylsulphonate; C1-C4-halogenated.sulphonated; optionally substituted phenyl group; optionally substituted fenoxaprop; optionally substituted phenylthiourea; optionally substituted aromatic heterocyclic group; optionally substituted aromatic heterocyclic actigraphy; optionally substituted aromatic heterocyclic diography; optional substituted phenylsulfinyl group; optionally substituted phenylsulfonyl group; not necessarily for amennye aromatic heterocyclic sulfonylurea group; optionally substituted phenylsulfonylacetate; acyl groups; C1-C4-galogenirovannyie group; optionally substituted benzylcarbamoyl group; optionally substituted benzoline group; carboxyl group; C1-C10-alkoxycarbonyl group; optionally substituted benzyloxycarbonyl group; optionally substituted phenoxycarbonyl group; cyano; carnemolla group (its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups and optionally substituted phenyl groups); C1-C6-alloctype; C1-C4-halogencarboxylic; optionally substituted benicarbenicar; optionally substituted benzoyloxy; the nitro-group and the amino group (with its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups, optionally substituted phenyl groups, C1-C6-acyl groups, C1-C6-halogencarboxylic groups, optionally substituted benzylcarbamoyl group, optionally substituted bentilee group, C1-C10-alkylsulfonyl group, C1-C4-halogenated.sulphonated groups, optionally substituted benzylaniline group and optionally substituted phenylsulfonyl group).

[Group Vice β]

Hydroxyl group;C3-C8-cycloalkyl group, which may be substituted by a halogen atom or alkyl group; C1-C10-alkoxygroup; C1-C10-allylthiourea; C1-C10-alkylsulfonyl group; C1-C10-alkoxycarbonyl group; C2-C6-halogenalkyls group; amino group (its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups, C1-C6-acyl groups, C1-C4-halogencarboxylic groups, C1-C10-alkylsulfonyl groups and C1-C4-halogenated.sulphonated groups); carnemolla group (and its the nitrogen atom may be substituted by identical or different C1-C10-alkyl groups; C1-C6-acyl groups; C1-C4-galogenirovannyie group; C1-C10-alkoxyimino; cyano; optionally substituted phenyl group, and optionally substituted fenoxaprop.

[Group Vice γ]

C1-C10-alkoxycarbonyl group; optionally substituted phenyl group; optionally substituted aromatic heterocyclic group; cyano; and carnemolla group (its nitrogen atom may be substituted by identical or different C1-C10-alkyl groups).

(2) Derived isoxazoline under item (1), where a group of deputies α heterocycle which may be substituted by 0 to 6 identical or different groups include a hydroxyl group; halogen atoms; C1-C10-alkyl groups; C1-C10-alkyl group is s, each monogamist group selected from the group of substituents β; C1-C4-halogenoalkane group; C3-C8-cycloalkyl group; C1-C10-alkoxygroup; C1-C10-alkoxygroup, each of which monogamist group selected from the group of substituents γ; C1-C4-halogenlampe; C3-C8-cycloalkylcarbonyl; C3-C8-cycloalkyl-C1-C3-alkyloxy; C1-C10-allylthiourea; C1-C10-allylthiourea, each of which monogamist group selected from group Vice γ; C1-C4-halogenation; C2-C6-alkeline group; C2-C6-alkenylacyl; C2-C6-alkyline group; C2-C6-alkyloxy; C1-C10-alkylsulfonyl group; C1-C4-galogenzameshchennye group; optionally substituted by fenoxaprop; optional substituted phenylthiourea; optionally substituted aromatic heterocyclic group; optionally substituted aromatic heterocyclic actigraphy; optionally substituted aromatic heterocyclic diography; optionally substituted phenylsulfonyl group; optionally substituted aromatic heterocyclic sulfonylurea group; C1-C6-acyl groups; C1-C4-galogenirovannyie group; optionally substituted benzylcarbamoyl group; optionally substituted benzoyloxy group; carboxyl group; C1-C10-alkoxycarbonyl the e group; the cyano; karbamoilnuyu group (its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups and optionally substituted phenyl group); a nitro-group and the amino group (its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups, optionally substituted phenyl groups, C1-C6-acyl groups, C1-C4-halogencarboxylic groups, optionally substituted benzylcarbamoyl group, optionally substituted bentilee group, C1-C10-alkylsulfonyl group, C1-C4-halogenated.sulphonated groups, optionally substituted benzylaniline group and optionally substituted phenylsulfonyl group); when the heterocyclic group is substituted in two adjacent positions by two alkyl groups, two alkoxygroup, alkyl group and alkoxygroup, alkyl group and alkylthiol, alkyl group and alkylsulfonyl group, alkyl group and monoalkylamines or alkyl group and dialkylamino, all of which are selected from the group of substituents α, two groups can form together with the atoms to which they are linked, 5-8-membered ring which may be substituted by 1-4 halogen atoms.

(3) Derived isoxazoline by p. (2), where a group of deputies α g is terracycle, which may be substituted by 0 to 6 identical or different groups include halogen atoms; C1-C10-alkyl groups; C1-C4-halogenoalkane group; C1-C10-alkoxy-C1-C3-alkyl groups; C3-C8-cycloalkyl group which may be substituted by a halogen atom or alkyl group; C1-C10-alkoxygroup; C1-C4-halogenlampe; C3-C8-cycloalkyl-C1-C3-alkyloxy; optional substituted fenoxaprop; C1-C10-allylthiourea; C1-C10-alkylsulfonyl group; acyl group; C1-C4-galogenirovannyie group; C1-C10-alkoxycarbonyl group; a cyano and karbamoilnuyu group (its nitrogen atom may be substituted by identical or different C1-C10-alkyl groups).

(4) Derived isoxazoline according to any one of paragraphs. (1), (2) or (3)where the substituents R1and R2may be the same or different and each represents methyl group or ethyl group; and each of the substituents R3, R4, R5and R6represents a hydrogen atom.

(5) Derived isoxazoline according to any one of paragraphs. (1), (2), (3) or (4)where Y represents a 5 - or 6-membered aromatic heterocyclic group containing a heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom.

(6) Derived isoxazoline under item (5), where Y represents a thienyl group, pyrazolidine group, isoxazol the ilen group, isothiazolinone group, pyridyloxy group or pyramidalnou group.

(7) Derived isoxazoline under item (6)where Y represents thiophene-3-ilen group, pyrazole-4-ilen group, a pyrazole-5-ilen group, isoxazol-4-ilen group, isothiazol-4-ilen group, pyridine-3-ilen group, or pyrimidine-5-ilen group.

(8) Derived isoxazoline under item (7), where Y is thiophene-3-ilen group, and thiophene ring at positions 2 and 4 substituted by the Deputy from the group of substituents α.

(9) Derived isoxazoline under item (7), where Y is a pyrazole-4-ilen group, pyrazol ring substituted in positions 3 and 5 Deputy from the group of substituents αand in position 1 atom of hydrogen, C1-C10-alkyl group, C1-C10-alkyl group monosubstituted by a group selected from the group of substituents β, C1-C4-halogenoalkanes group, C3-C8-cycloalkyl group, C2-C6-alkenylphenol group, C2-C6-alkenylphenol group C1-C10-alkylsulfonyl group, C1-C10-alkylsulfonyl group, C1-C10-alkylsulfonyl group monosubstituted by a group selected from the group of substituents γ, C1-C4-halogenated.sulphonated group optionally substituted phenyl group, optionally substituted aromatic heterocyclic group, optionally substituted phenylsulfonyl group, long is correctly substituted aromatic heterocyclic sulfonyloxy group, acyl group, C1-C4-halogencarboxylic group, optionally substituted benzylcarbamoyl group, optionally substituted bentilee group, C1-C10-alkoxycarbonyl group, optionally substituted benzyloxycarbonyl group, optionally substituted phenoxycarbonyl group, carbamoyl group (its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups and optionally substituted phenyl group), or an amino group (its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups, optionally substituted phenyl groups, acyl groups, C1-C4-halogencarboxylic groups, optionally substituted benzylcarbamoyl group, optionally substituted bentilee group, C1-C10-alkylsulfonyl groups, C1-C4-halogenated.sulphonated groups, optionally substituted benzylaniline group and optionally substituted phenylsulfonyl group).

(10) Derived isoxazoline under item (7), where Y is a pyrazole-5-ilen group, pyrazol ring substituted in position 4 by a Deputy from the group of substituents αand in position 1 atom of hydrogen, C1-C10-alkyl group, C1-C10-alkyl group monosubstituted by a group selected from the group of Deputy is th β , C1-C4-halogenoalkanes group, C3-C8-cycloalkyl group, C2-C6-alkenylphenol group, C2-C6-alkenylphenol group, C1-C10-alkylsulfonyl group, C1-C10-alkylsulfonyl group, C1-C10-alkylsulfonyl group monosubstituted by a group selected from the group of substituents γ, C1-C4-halogenated.sulphonated group optionally substituted phenyl group, optionally substituted aromatic heterocyclic group, optionally substituted phenylsulfonyl group, optionally substituted aromatic heterocyclic sulfonyloxy group, acyl group, C1-C4-halogencarboxylic group, optionally substituted benzylcarbamoyl group, optionally substituted bentilee group, C1-C10-alkoxycarbonyl group, optionally substituted benzyloxycarbonyl group, optionally substituted phenoxycarbonyl group, carbamoyl group (its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups and optionally substituted phenyl group), or an amino group (its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups, optionally substituted phenyl groups, acyl groups, C1-C4-halogencarboxylic groups, not necessarily samewe the Noah benzylcarbamoyl group, optionally substituted bentilee group, C1-C10-alkylsulfonyl groups, C1-C4-halogenated.sulphonated groups, optionally substituted benzylaniline group and optionally substituted phenylsulfonyl group).

(11) Derived isoxazoline under item (7), where Y is isoxazol-4-ilen group, and isoxazoline ring substituted in positions 3 and 5 Deputy from the group of substituents α. (12) Derived isoxazoline under item (7), where Y is isothiazol-4-ilen group, isothiazol ring substituted in positions 3 and 5 Deputy from the group of substituents α.

(13) Derived isoxazoline under item (7), where Y is a pyridine-3-ilen group and the pyridine ring is substituted in positions 2 and 4 Deputy from the group of substituents α.

(14) Derived isoxazoline under item (7), where Y is a pyrimidine-5-ilen group, and a pyrimidine ring substituted in positions 4 and 6 Deputy from the group of substituents α.

(15) Derived isoxazoline according to any one of paragraphs. (1)to(14), where n is equal to 2.

(16) Derived isoxazoline according to any one of paragraphs. (1)to(14), where n is equal to 1.

(17) Derived isoxazoline according to any one of paragraphs. (1)to(14), where n is equal to 0.

(18) a Herbicide containing as an active ingredient derived isoxazoline presented in any of paragraphs. (1)to(17), or its pharmaceutically when mleay salt.

Detailed description of the invention

Definition of terms used in this description below.

The expression "C1-C10", etc. shows that Deputy appearing after this expression contains from 1 to 10 carbon atoms in the case of "C1-C10".

The halogen atom means a fluorine atom, chlorine atom, bromine atom or iodine atom.

The definition of "C1-C10-alkyl group" refers to linear or branched alkyl group of 1-10 carbon atoms, unless otherwise noted; can be called, for example, methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, isopentyl group, neopentyl group, n-exilda group, isohexyl group, 3,3-dimethylbutyl group, heptylene group and anjilina group.

The definition of "C3-C8-cycloalkyl group" refers to cycloalkyl group of 3-8 carbon atoms; can be called, for example, cyclopropyl group, cyclobutyl group, cyclopentenone group and tsiklogeksilnogo group.

The definition of "C3-C8-cycloalkyl-C1-C3-alkyl group (which may be substituted by a halogen atom or alkyl group), unless otherwise noted, refers to C1-C3-alkyl group, a substituted C3-C8-cycloalkyl group, colorature to be substituted by 1-4 identical or different halogen atoms or C1-C3-alkyl group; can be named, for example, cyclopropylmethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 1-cyclopropylamino group, 2-cyclopropylamino group, 3-cyclopropylamino group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, 2-chlorocyclopropane group, 2,2-dichlorocyclopentane group, 2-tortilleria group, 2,2-defencecapabilities group, 2-methylcyclopropyl group, 2,2-dimethylcyclopropane group and 2-methylcyclopropyl group.

The definition of "C3-C8-cycloalkyl-C1-C3-alkyl group" refers to an alkyl group of 1-3 carbon atoms, substituted cycloalkyl group of 3-8 carbon atoms; can be called, for example, cyclopropylmethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 1-cyclopropylamino group, 2-cyclopropylamino group, 3-cyclopropylamino group, cyclobutylmethyl group, cyclopentylmethyl group and cyclohexylmethyl group.

The definition of "C1-C4-halogenation group" refers, unless otherwise noted, linear or branched alkyl group of 1-4 carbon atoms, substituted 1-9 identical or different halogen atoms; can be called, for example, permetrina group, chloromethyl the Naya group, brometalia group, deformational group, triptorelin group, 2,2-deperately group, 2,2,2-triptorelin group and panafcortelone group.

The definition of "C2-C6-Alchemilla group" refers to linear or branched alkenylphenol group of 2-6 carbon atoms; can be called, for example, Attila group, 1-protanilla group, 2-protanilla group, Isopropenyl group, 1-bucinellina group, 2-bucinellina group, 3-bucinellina group and 2-penttila group.

The definition of "C2-C6-Alchemilla group" refers to linear or branched alkenylphenol group of 2-6 carbon atoms; can be called, for example, etinilnoy group, 2-proponila group, 1-methyl-2-proponila group, 2-Butyrina group, 3-Butyrina group and 2-methyl-3-Butyrina group.

The definition of "C2-C6-halogenation group" refers, unless otherwise noted, linear or branched alkenylphenol group of 2-6 carbon atoms, substituted by 1-4 identical or different halogen atoms; can be called, for example, 3-chloro-2-protanilla group and 2-chloro-2-protanilla group.

The definition of "C1-C10-alkoxygroup" refers to (alkyl)-O-group, where the alkyl residue is as defined above values and can be called, for example, a methoxy group, ethoxypropan, n-propoxylate, isopropoxide, tert-BU is oxygraph, n-butoxypropyl, second-butoxypropan and isobutoxy.

The definition of "C1-C4-halogenlampe" refers to (halogenated)-O-group, where allogeneically the residue defined above values; can be called, for example, dipterocarp, cryptometer, 2,2-dipterocarp and 2,2,2-triptracker.

The definition of "C3-C8-cycloalkylation" refers to (cycloalkyl)-O-group, where cycloalkenyl the residue defined above values; can be called, for example, cyclopropylamino, cyclobutylamine, cyclopentylamine and cyclohexyloxy.

The definition of "C3-C8-cycloalkyl-C1-C3-alkyloxy" refers to (cycloalkenyl)-O-group, where cycloalkylcarbonyl the residue defined above values; and may be called, for example, cyclopropylmethoxy, 1-cyclopropylmethoxy, 2-cyclopropylethyl, 1-cyclopropylmethoxy, 2-cyclopropanecarboxylate, 3-cyclopropylmethoxy, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

The definition of "C2-C6-alkenylacyl" and "C2-C6-alkynylamino", respectively, refer to (alkenyl)-O-group and (quinil)-O-group, each of which alkanniny or alkynylaryl the residue defined above values; can be called, for example, 2-propenyloxy the PAP and 2-propenyloxy.

The definition of "C1-C10-alkoxyimino" refers to (alkoxy)-N-group, where alkoxylate has the above specified values; can be called, for example, methoxyimino and toksikologiya.

The definition of "C1-C10-allylthiourea", "C1-C10-alkylsulfonyl group" and "C1-C10-alkylsulfonyl group", respectively, refer to (alkyl)-S-group, (alkyl)-SO-group and (alkyl)-SO2group, each of which alkyl residue is as defined above values; can be called, for example, methylthiourea, ethylthiourea, n-PropertyGroup, isopropylthio, methylsulfinyl group, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group and isopropylaniline group.

The definition of "C1-C10-alkylsulphonate" refers to (alkylsulfonyl)-O-group, where alkylsulfonyl the residue defined above values; can be called, for example, methylsulfonylamino and arilsulfonilglitsinov.

The definition of C1-C10-alkoxycarbonyl group belongs to (alkoxy)-CO-group in which alkoxylate has the above specified values, and can be named, for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group and isopropoxycarbonyl group.

The definition of "C1-C6-acyl group" refers to linear and the branched aliphatic acyl group of 1-6 carbon atoms, and can be called, for example, formyl group, acetyl group, propylaniline group, isopropylidene group, Butyrina group and pivellina group.

The definition of "C1-C10-alkoxygroup" refers to (acyl)-O-group in which the acyl residue is as defined above values; can be called, for example, acetoxygroup, propionyloxy, isopropenylacetate and pivaloyloxy.

The definition of "C1-C4-halogencarbonic group", "C1-C4-halogenlampe" and "C1-C4-halogenated.sulphonated group" refer respectively to (halogenated)-CO-group (halogenated)-S-group and (halogenated)-SO2group, each of which allogeneically the residue defined above values, and can be named, for example, chlorocichla group, trifluoracetyl group, pentafluoropropyl group, deformationof, triptoreline, chloromethanesulfonyl group, diplomatically group and triftormetilfullerenov group.

The definition of "C1-C4-halogencarboxylic" and "C1-C4-halogenated.sulphonated" respectively refer to (halogenoalkanes)-O-group and (halogenallylacetic)-O-group, each of which halogencarboxylic balance or halogenated.sulphonated the residue defined above; and m which may be called, for example, chloroacetoxy, triftoratsetilatsetonom, chlorotrimethylsilane and triftormetilfullerenov.

The definition of "optionally substituted" in the definition (optionally substituted) phenyl group (optionally substituted) aromatic heterocyclic group (optionally substituted) fenoxaprop, (optionally substituted) aromatic heterocyclic oxygraph, (optionally substituted) phenylthiourea, (optionally substituted) aromatic heterocyclic tighrope, (optionally substituted) phenylsulfonyl group, (optionally substituted) phenylsulfonylacetate, (optionally substituted) aromatic heterocyclic sulfonylurea group, (optionally substituted) benzylcarbamoyl group, (optionally substituted) benzylcarbamoyl, (optionally substituted) benzylaniline group, (optionally substituted) benzoline group, (optionally substituted) benzoyloxy, (optionally substituted) benzyloxycarbonyl group and (optionally substituted) phenoxycarbonyl group, refers to a group, optionally substituted, e.g. by halogen atom, C1-C10-alkyl group, C1-C4-halogenoalkanes group, C1-C10-alkoxyalkyl group, C1-C10-alkoxygroup, C1-C10-alkylthiol, C1-C0-alkylsulfonyl group, acyl group, C1-C10-alkoxycarbonyl group, cyano, carbamoyl group (its nitrogen atom may be substituted by identical or different C1-C10-alkyl groups), nitro-group or amino group (its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups, C1-C6-acyl groups, C1-C4-halogencarboxylic groups, C1-C10-alkylsulfonyl groups and C1-C4-halogenated.sulphonated groups).

The definition of "5-6-membered aromatic heterocyclic group containing a heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom"includes, for example, follow group, thienyl group, pyrrolidino group, pyrazolidine group, isoxazolyl group, isothiazolinone group, oxazolidinyl group, thiazolidine group, imidazolidinyl group, pyridyloxy group, pyridazinyl group, pyrimidinyl group, personilnya group, triazinyl group, triazolyl group, oxadiazolyl group and thiadiazolyl group, each of which contains 1-3 heteroatoms.

The definition of "condensed aromatic heterocyclic group" refers to a group containing from 1 to 3 heteroatoms arbitrarily selected from nitrogen atom, oxygen atom and sulfur atom; can be called, for example, benzoperylene group, benzocain is supplemented flax group, indlela group, benzoxazolyl group, benzothiazolyl group, benzimidazolyl group, benzisoxazole group, benzisothiazolinone group, indazolinone group, kinolinna group, izochinolina group, phthalazinone group, khinoksalinona group, chinadaily group, indolenine group and benzothiazolyl group.

The definition of "aromatic heterocycle (optionally substituted) aromatic heterocyclic group (optionally substituted) aromatic heterocyclic exigrep, (optionally substituted) aromatic heterocyclic tighrope and (optionally substituted) aromatic heterocyclic sulfonyloxy group, refers to a 5-6-membered group containing from 1 to 3 heteroatoms, selected randomly from nitrogen atom, oxygen atom and sulfur atom; can be called, for example, furilla group, thienyl group, pyrrolidine group, pyrazolidine group, isoxazolyl group, isothiazolinone group, oxazoline group, thiazolidine group, imidazolidinyl group, perederina group, pyridazinyl group, pyrimidinyl group, piratininga group, trainline group, thiazolidine group, oxadiazolyl group and thiadiazolidine group.

Pharmaceutically acceptable salt is a salt is soedineniya General formula [I], containing in the structure a hydroxyl group, carboxyl group, amino group or other such group, with metal or organic base or with a mineral acid or an organic acid. As metals can be called alkali metals such as sodium, potassium, etc. and alkaline earth metals such as magnesium, calcium, etc. as organic bases can be called triethylamine, Diisopropylamine and other mineral acids may be mentioned hydrochloric acid, sulfuric acid and other organic acids can be called acetic acid, methanesulfonate acid, p-toluensulfonate acid and other

In the above formula [I] preferably, when

R1and R2may be the same or different and each represents methyl group or ethyl group;

each of R3, R4, R5and R6represents a hydrogen atom;

n is 2; and

Y represents thiophene-3-ilen group [2 - and 4-th position group substituted by the same or different groups selected from halogen atoms, alkyl groups, halogenating groups, alkoxyalkyl groups, cycloalkyl groups, alkoxygroup, halogenlamp, acyl groups, halogencarboxylic groups, alkoxycarbonyl groups, cyano groups and carbamoyl Inoi group (its nitrogen atom may be substituted by the same or different alkyl groups)], or

pyrazole-4-ilen group [3 - and 5-th position group substituted by the same or different groups selected from halogen atoms, alkyl groups, halogenating groups, alkoxyalkyl groups, cycloalkyl groups, alkoxygroup, halogenlamp, cycloalkylcarbonyl, optionally substituted fenoxaprop, alkylthio, alkylsulfonyl groups, acyl groups, halogencarboxylic groups, alkoxycarbonyl groups, cyanopropyl and carbamoyl group (its nitrogen atom may be substituted by the same or different alkyl groups); the 1st position is substituted by a hydrogen atom, alkyl group, alkyl group monosubstituted by a group selected from group Vice β, halogenoalkanes group, cycloalkyl group, alkenylphenol group, alkenylphenol group, alkylsulfonyl group, alkylsulfonyl group monosubstituted by a group selected from the group of substituents γ, halogencontaining group optionally substituted phenyl group, optionally substituted aromatic heterocyclic group, optionally substituted phenylsulfonyl group, optionally substituted aromatic heterocyclic sulfonyloxy group, acyl group, halogencarboxylic group, optionally substituted benzylcarbamoyl what Ruppel, optionally substituted bentilee group, alkoxycarbonyl group, optionally substituted benzyloxycarbonyl group, optionally substituted phenoxycarbonyl group or carbamoyl group (its nitrogen atom may be substituted by identical or different groups selected from alkyl groups and optionally substituted phenyl group)], or

pyrazole-5-ilen group [4-th position of the group substituted by halogen atom, alkyl group, halogenoalkanes group, alkoxyalkyl group, halogenlampe, acyl group, halogencarboxylic group, alkoxycarbonyl group, a cyano or carbamoyl group (its nitrogen atom may be substituted by the same or different alkyl groups); the 1st position is substituted by a hydrogen atom, alkyl group, alkyl group monosubstituted by a group selected from the group of substituents β, halogenoalkanes group, cycloalkyl group or optionally substituted phenyl group], or

isoxazol-4-ilen group [3 - and 5-th position group substituted by the same or different groups selected from halogen atoms, alkyl groups, halogenating groups, alkoxyalkyl groups, cycloalkyl groups, alkoxygroup, halogenlamp, alkylthio, alkylsulfonyl acyl groups the groups, halogencarboxylic groups, alkoxycarbonyl groups, cyanopropyl and carbamoyl group (its nitrogen atom may be substituted by the same or different alkyl groups)], or

isothiazolin-4-ilen group [3 - and 5-th position group substituted by the same or different groups selected from halogen atoms, alkyl groups, halogenating groups, alkoxyalkyl groups, cycloalkyl groups, alkoxygroup, halogenlamp, optionally substituted fenoxaprop, alkylthio, alkylsulfonyl groups, acyl groups, halogencarboxylic groups, alkoxycarbonyl groups, cyanopropyl and carbamoyl group (its nitrogen atom may be substituted by the same or different alkyl groups)], or

pyridine-3-ilen group [2 - and 4-th position group substituted by the same or different groups selected from halogen atoms, alkyl groups, halogenating groups, alkoxyalkyl groups, cycloalkyl groups, alkoxygroup, halogenlamp, alkylthio, alkylsulfonyl groups, acyl groups, halogencarboxylic groups, alkoxycarbonyl groups, cyanopropyl and carbamoyl group (the nitrogen atom may be substituted by the same or different alkyl groups)], or

pyrimidine-5-ilen group [(4 - and 6-th position group substituted by the same or is asnami groups, selected from halogen atoms, alkyl groups, halogenating groups, alkoxyalkyl groups, cycloalkyl groups, alkoxygroup, halogenlamp, alkylthio, alkylsulfonyl groups, acyl groups, halogencarboxylic groups, alkoxycarbonyl groups, cyanopropyl and carbamoyl group (its nitrogen atom may be substituted by the same or different alkyl groups)].

Next, typical examples of the compounds of the present invention represented by formula [I]shown in tables 1-10. However, this connection is not limited to these examples.

Below abbreviated expressions used in the tables refer to the following groups:

Ph is a phenyl group
IU - methyl groupEt is ethyl group
Pr - n-through groupPr-i - ISO-propyl group
Pr-c - cyclopropylidene groupBu - n-bucilina group
Bu-i - isobutylene groupBu-s - second-bucilina group
Bu-t t - bucilina groupBu-c - cyclobutyl group
Pen - n-pencilina groupPen-c - cyclopentenone group
Hex - exilda groupHex-c - tsiklogeksilnogo group

For example, (4-Cl)Ph means 4-chloraniline group and 3-Hex means 3-hexoloy group.

When the present invention contains a hydroxyl group as a substituent, there may be keto-enol tautomers. Any of these tautomers and any mixtures of these tautomers refer to this connection.

The compound of the present invention represented by the General formula [I]can be obtained in accordance with the methods presented below; however, the connection can also be obtained in other ways.

<a Method of obtaining 1>

Stage 1 - stage 5

In the above scheme, obtaining the substituents R1, R2, R3, R4, R5, R6and Y have the definitions given above; X1represents a halogen atom; R7represents C1-C4-alkyl group, optionally substituted phenyl group or optionally substituted benzyl group; L represents a leaving group such as halogen atom, C1-C4-alkylsulfonyl group, optionally substituted phenylsulfonyl group, optionally substituted benzylaniline group and others; integer x is 1 or more.

The above method of obtaining described below in more detail at each stage.

(Stage 1)

Sulfide derivative represented by General formula [5]can be obtained by reaction of the compound represented by the General formula [1], with hydrate of sodium hydrogen sulfide represented by the General formula [2], in the presence or in the absence of a solvent (preferably in a suitable solvent in the presence of salt with getting the base of the mercaptan represented by the General formula [3], in the reaction system, and then without releasing salt of the mercaptan [3] is introduced into the reaction with the halogenated derivative represented by the General formula [4] (in this case, it may be added agent, forming radical, for example rongalit: CH2(HE)SO2Na.2H2O).

The reaction temperature in each reaction is equal to any temperature between 0°and a boiling point under reflux for each reaction system, and preferably equal to 10-100°C. the reaction Time varies depending on the connection, and is usually from 0.5 to 24 hours.

As for the quantities used in each reaction reagents, each connection represented by the General formula [2]and the compound represented by the General formula [4], are used in quantities of from 1 to 3 equivalents per equivalent of the compound represented by the General formula [1], and when used the ground, it is used in quantities of from 0.5 mm to 3 equivalents.

The solvent includes, for example, ethers such as dioxane, tetrahydrofuran (THF), etc.; halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and others; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and others; sulfur compounds such as dimethylsulfoxide, sulfolane and so on; aromatic hydrocarbons such as benzene, toluene, xylene and so on; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol and so on; ketones such as acetone, 2-butanone, etc.; NITRILES, such as acetonitrile, etc.; water, and mixtures thereof.

As a basis you can use, for example, metal hydrides such as sodium hydride and so on; amides of alkali metals such as sodium amide, diisopropylamide lithium and so on; organic bases, such as pyridine, triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene etc.; hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, etc.; hydroxides of alkaline earth metals such as calcium hydroxide, magnesium hydroxide, etc.; carbonates of alkali metals such as sodium carbonate, potassium carbonate, etc.; bicarbonates of alkali metals, such as sodium bicarbonate, potassium bicarbonate, etc. and a metal alcoholate such as sodium methoxide, tert-piperonyl potassium, etc./p>

(Stage 2)

Sulfoxide derivative represented by the General formula [6]can be obtained by the reaction of sulfide derivative represented by General formula [5]with an oxidizing agent in a suitable solvent.

The reaction temperature is equal to any temperature between 0°and a boiling point under reflux for each reaction system, and preferably equal 0-60°C. the reaction Time varies depending on connection and is usually from 1 to 72 hours.

Regarding the amounts of reagents used in each reaction, the oxidizing agent is used in an amount of from 1 to 3 equivalents per equivalent of the compound represented by the General formula [5].

The solvent includes, for example, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and so on; ethers such as dioxane, tetrahydrofuran (THF), dimethoxyethane, diethyl ether, and others; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and others; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol and so on; ketones such as acetone, 2-butanone, etc.; NITRILES, such as acetonitrile, etc.; acetic acid; water, and mixtures thereof.

As the oxidizing agent can be called, in the example, organic peroxides such as m-chlormadinone acid, nagarajuna acid, peracetic acid, etc. and inorganic peroxides such as hydrogen peroxide, potassium permanganate, periodate sodium, etc.

(Stage 3)

Sulfonic derivative represented by the General formula [7]can be obtained by the reaction sulfoxide derivative represented by the General formula [6]with an oxidizing agent in a suitable solvent.

The reaction temperature is equal to any temperature between 0°and a boiling point under reflux the reaction system and preferably equal 0-60°C. the reaction Time varies depending on connection and is usually from 1 to 72 hours.

Regarding the amounts of reagents used in the reaction, the oxidizing agent is used in an amount of from 1 to 3 equivalents per equivalent of the compound represented by the General formula [6].

As solvent and oxidizing agent can be mentioned the same solvents and oxidizing agents, which are listed for stage 2.

(Stage 4)

Sulfonic derivative represented by the General formula [7]can be obtained by the reaction of sulfide derivative represented by General formula [5], with the appropriate amount of oxidizing agent in a suitable solvent without isolating the su is hoxeng derivative, represented by the General formula [6].

The reaction temperature is equal to any temperature between 0°and a boiling point under reflux the reaction system and preferably equal 0-60°C. the reaction Time varies depending on connection and is usually from 1 to 72 hours.

Regarding the amounts of reagents used in the reaction, the oxidizing agent is used in an amount of from 1 to 3 equivalents per equivalent of the compound represented by the General formula [5].

As solvent and oxidizing agent can be mentioned the same solvents and oxidizing agents, which are listed for stage 2.

(Stage 5)

Sulfide derivative represented by General formula [5]can be obtained by reaction of the compound represented by the General formula [8], with mercaptanes derivative represented by the General formula [9], in the presence or in the absence of a solvent (preferably in a suitable solvent in the presence of a base.

The reaction temperature is equal to any temperature between 0°and a boiling point under reflux the reaction system and is preferably from 10 to 100°C. the reaction Time varies depending on the compounds and ranges from 0.5 to 24 czasowe refers to the quantities used in the reaction of the reagents, the connection, before the purposes of the General formula [9], is used in an amount of from 1 to 3 equivalents per equivalent of the compound represented by the General formula [8], and the base is used in an amount of from 0.5 to 3 equivalents.

The solvent includes, for example, ethers such as diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran (THF), etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene and others; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone etc.; sulfur-containing compounds such as dimethylsulfoxide, sulfolane and so on; aromatic hydrocarbons such as benzene, toluene, xylene and so on; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol and so on; ketones such as acetone, 2-butanone, etc.; NITRILES, such as acetonitrile, etc.; water, and mixtures thereof.

As grounds include, for example, metal hydrides such as sodium hydride and so on; amides of alkali metals such as sodium amide, diisopropylamide lithium and so on; organic bases, such as pyridine, triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene etc.; hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, etc.; hydroxides of alkaline earth metals such as calcium hydroxide, magnesium hydroxide, etc.; carbonates SEL is cnyh metals, such as sodium carbonate, potassium carbonate, etc.; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, etc. and a metal alcoholate such as sodium methoxide, tert-piperonyl potassium, etc.

The compound of General formula [8], in which L represents a halogen atom, i.e. a compound [12]can be obtained by a method represented by the following stage 6. If necessary, the mixture of compounds [12] and the compound [13] is subjected to separation and purification with the aim of identifying compounds [12].

(Stage 6)

In the above reaction, the substituents X1, R1, R2, R3and R4have the same definitions given above.

Isoxazoline compounds represented by the General formula [12] and [13], can be obtained by the reaction of olefinic derivative represented by the General formula [10], oxime derivative represented by the General formula [11], in the presence or in the absence of a solvent (preferably in a suitable solvent in the presence of a base. When each of the substituents R3and R4represents a hydrogen atom, preferably can be obtained isoxazoline the connection represented by the General formula [12].

The reaction temperature is equal to any temperature between 0°and a boiling point from about the military refrigerator reaction system and is preferably from 10 to 80° C. the reaction Time varies depending on the compounds ranging from 0.5 hour to 2 weeks.

As for the quantities used in the reaction of the reagents, the compound represented by the General formula [10], is used in an amount of from 1 to 3 equivalents to one equivalent of the compound represented by the General formula [11].

The solvent includes, for example, ethers such as dimethyl ether of ethylene glycol, diethyl ether of ethylene glycol, diethyl ether, dioxane, tetrahydrofuran and so on; halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and so on; aromatic hydrocarbons such as benzene, toluene, xylene and so on; esters of acetic acid such as ethyl acetate, butyl acetate, etc.; water, and mixtures thereof.

As grounds include, for example, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, etc.; hydroxides of alkaline earth metals such as calcium hydroxide, magnesium hydroxide, etc.; carbonates of alkali metals such as sodium carbonate, potassium carbonate, etc.; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, etc.; acetates of alkali metals such as sodium acetate, potassium acetate and others; alkali metal fluorides such as sodium fluoride, potassium fluoride the other; and organic bases, such as pyridine, triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene and other

In the above method of obtaining the compound represented by the General formula [10], used as intermediate compounds, may be available for sale or can be obtained by known reactions such as Wittig reaction or other Compound represented by the General formula [11]can be obtained, for example, by the method described in Liebigs Annalen der Chemie, 985 (1989).

The connection represented by the General formula [1], can be obtained from the above-mentioned compounds represented by the General formula [12], in the following way.

In the above reaction, the substituents X1, R1, R2, R3, R4and R7have the definitions given above.

The connection represented by the General formula [15]can be obtained using the above stage 5; a compound represented by the General formula [16], can be obtained in the above stage 2, and the compound represented by the General formula [1]can be obtained from compound [15] using the above stage 4 or of compounds [16] using the above stage 3.

As the solvent, base and oxidizing agent can be used the same solvents, bases and oxidizing agents, which was the lists for stages 2, 3, 4 or 5.

The connection represented by the General formula [4], where the substituent R6represents a hydrogen atom, i.e. a compound represented by the General formula [21], can be obtained in the following way.

In the above reaction, the substituents R5X1and Y have the definitions given above, and the substituent R8represents an alkyl group.

(Stage 11)

The connection represented by the General formula [20]can be obtained by reaction of the compound [17], [18] or [19] with a regenerating agent in a solvent.

This reaction is usually carried out at a temperature of from -60 to 150°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, the reducing agent is used in amounts of preferably from 0.5 to 2 equivalents per equivalent of the compound [17], [18] or [19]; however, the number may vary accordingly depending on the reaction conditions.

As the reducing agent can be named, for example, metal hydrides (e.g., diisobutylaluminium) and complex compounds of metals and hydrogen (for example, borohydride sodium and sociallyengaged), when the connection [20] from the compound [17], and metal hydrides (for example, diisobutylaluminium), complex compounds of metals of vodoroda (for example, borohydride sodium and sociallyengaged) and DIBORANE, when the connection [20] from the compound [18] or [19].

The solvent includes, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane and so on; aromatic hydrocarbons such as benzene, toluene, etc. and alcohols, such as methanol, ethanol, etc.

(Stage 12)

The connection represented by the General formula [21], can be obtained by reaction of the compound [20] with a halogenation agent in a solvent.

This reaction is usually carried out at a temperature of from -50 to 100°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, the halogenation agent is used in amounts of preferably from 1 to 3 equivalents per equivalent of the compound [20]; however, the number may vary accordingly depending on the reaction conditions.

As the halogenation agent include, for example, hydrogen chloride, hydrogen bromide, trichloride phosphorus, tribromide phosphorus and thionyl chloride.

The solvent can be mentioned, for example, halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, etc.; acids such as acetic acid, etc. and ethers, such as tetrahydrofuran, etc.

The connection represented by the General formula [4]can be obtained in the following ways the om.

In the above reaction, the substituents R5, R6X1and Y have the definitions given above.

The connection represented by the General formula [4]can be obtained by reaction of the compound [22] with a halogenation agent in a solvent in the presence or in the absence of a catalyst.

This reaction is usually carried out at a temperature of from 30 to 150°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, the halogenation agent is used in amounts of preferably from 1 to 10 equivalents to one equivalent of the compound [22]; however, the number of halogenation agent may vary accordingly depending on the reaction conditions. The catalyst is used in quantities of from 0.01 to 0.5 equivalents.

As the halogenation agent can be named, for example, halogen, such as bromine, chlorine, etc.; N-halogenating, such as N-bromosuccinimide, etc. and pyridine salts, such as perbromide pyridinium etc.

The solvent can be named, for example, halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and so on; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone etc.; sulfur-containing compounds such as dimethylsulfoxide, sulfolan etc., the carboxylic acid, such as formic acid, acetic acid, etc.

As the catalyst can be named, for example, benzoyl peroxide, α,α-azobisisobutyronitrile, and their mixture.

The connection represented by the General formula [4], in which each of the substituents R5and R6represents a hydrogen atom, i.e. a compound represented by the General formula [24], can be obtained in the following way.

In the above reaction, the substituents X1and Y have the definitions given above.

The connection represented by the General formula [24], can be obtained by reaction of the compound [23], hydrogen halide and formaldehyde or paraformaldehyde in a solvent in the presence or in the absence of a Lewis acid according to the method described in publications Org. Synth., III, 557 (1955), or J. Am. Chem. Soc., 72, 2216 (1950), or in the interaction of compounds [23] halogenation ether in a solvent in the presence of a Lewis acid according to the method described in the publication J. Am. Chem. Soc., 97, 6155 (1975).

This reaction is usually carried out at temperatures from -40 to 150°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reactants, hydrogen halide, formaldehyde, paraform, Lewis acid or halogenosilanes ether used in the amount of gelatelno 1 to 2 equivalents per equivalent of the compound [23]; however, the first number may vary accordingly depending on the reaction conditions.

As the Lewis acid includes, for example, titanium tetrachloride, zinc chloride, aluminum chloride and zinc bromide.

As the hydrogen halide can be called chloride hydrogen bromide hydrogen and iodine hydrogen.

The solvent can be named, for example, halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chloroform, and so on; aliphatic hydrocarbons such as hexane, heptane and so on; ethers such as dioxane, tetrahydrofuran, etc.; carboxylic acids such as acetic acid, etc.; carbon disulphide, and mixtures thereof.

The connection represented by the General formula [19], in which the substituent R5represents a hydrogen atom, i.e. a compound represented by the General formula [25], can be obtained in the following way.

In the above reaction, the substituents Y have the definitions given above.

The connection represented by the General formula [25], can be obtained by reaction of the compound [23] with N,N-dimethylformamide in the presence of phosphorylchloride, phosgene or thionyl chloride in the presence or in the absence of solvent on Vilsmeier, as described in Org. Synth., IV, 831 (1963), or when interacting compounds [23] di is halogenosilanes ether in a solvent in the presence of a Lewis acid and then carrying out hydrolysis in accordance with the method described in Chem. Ber., 93, 88 (1960).

This reaction is usually carried out at temperatures from -40 to 150°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, phosphorylchloride, phosgene, thionyl chloride, N,N-dimethylformamide, a Lewis acid or halogenosilanes ether used in amounts of preferably from 1 to 2 equivalents per equivalent of the compound [23]; however, the first number may vary accordingly depending on the reaction conditions.

As the Lewis acid includes, for example, titanium tetrachloride, tin tetrachloride, zinc chloride, aluminum chloride and zinc bromide.

The solvent can be named, for example, halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chloroform, and so on; aliphatic hydrocarbons such as hexane, heptane and so on; ethers such as dioxane, tetrahydrofuran, etc.; carboxylic acids such as acetic acid and so on; amides such as N,N-dimethylformamide, etc.; carbon disulphide, and mixtures thereof.

Compounds represented by the General formula[17], [18], [19] and [20] can be obtained in the following way.

In the above reaction, the substituents R5, R8and Y have the definitions given above, the X 2represents a chlorine atom, a bromine atom or an iodine atom.

Compounds represented by the General formula[17], [18], [19] and [20], can be obtained by reaction of the compound [26] with magnesium reagent in the presence or in the absence of solvent, to obtain the compounds [27], and then in the interaction of compounds [27] with an electrophilic reagent in accordance with the method described in J.Org. Chem., 65, 4618 (2000), or when interacting compounds [26] c n-butyllithium in a solvent to obtain compounds [28], and then by reaction of the compound [28] with an electrophilic reagent in accordance with the method described in Synth. Commun., 24(2), 253 (1994).

This reaction is usually carried out at a temperature of from -100 to 150°C for 10 minutes to 24 CASCO refers to the quantities used in the reaction of the reagents, the amount of magnesium reagent or a lithium reagent is preferably from 1 to 5 equivalents per equivalent of the compound [26], and the number of electrophilic reagent is preferably from 1 to 5 equivalents; however, these amounts may vary accordingly depending on the reaction conditions.

As the magnesium reagent include, for example, magnesium metal, isopropylacrylamide and Diisopropylamine.

As a lithium reagent can be called, for example, n-utility, second-utility and tert-utility.

In ka is este electrophilic reagent may be named for example, esters such as ethyl formate, ethylcyanoacrylate, ethyl acetate and so on; acid halides such as acetylchloride, methylchloroform and so on; amides such as N,N-dimethylformamide, etc.; aldehydes such as paraformaldehyde, etc. and carbon dioxide.

As solvents can be named, for example, halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chloroform, and so on; aliphatic hydrocarbons such as hexane, pentane, etc.; ethers, such as dioxane, tetrahydrofuran, etc. and mixtures thereof.

Among the compounds represented by the General formula[4], [17], [18], [19], [20], [22], [23], [26], [29] or [34], the compound represented by the General formula [31]can be obtained in the following way.

In the above reaction Y have the definitions given above; R9represents an alkyl group, halogenation group, cycloalkyl group, cycloalkenyl group, alkoxycarbonyl group, optionally substituted benzyl group, optionally substituted heterocyclic alkyl group, alkenyl, optionally substituted heterocyclic alkyl group, alkenylphenol group, alkylamino group, alkylsulfonyl group, halogenated.sulphonated group, optionally substituted, aromati the definition heterocyclic group, optionally substituted phenylsulfonyl group, acyl group, halogencarbonic group, optionally substituted benzylcarbamoyl group or optionally substituted benzoyloxy group; and L1represents a leaving group such as halogen atom, C1-C4-alkylsulfonate group, C1-C4-alkylsulfonyl group, optionally substituted benzylaniline group, optionally substituted phenylsulfonyl group, optionally substituted benzylmalonate group, etc. When the substituent R9represents halogenating group, L1represents a leaving group, with a higher reactivity than the halogen atom, the remaining after halogenoalkane. For example, when the substituent R9represents CHF2group, L1represents a chlorine atom or a bromine atom, and when the substituent R9represents CH2CF3group, L1represents a chlorine atom, a bromine atom, p-toluensulfonate or methylsulfonylamino.

The connection represented by the General formula [31]can be obtained by the reaction of compound [29] with the compound [30] in a solvent in the presence of a base.

This reaction is usually carried out at temperatures from 0 to 120°C for from 10 min to 24 hours.

H what about the concerns of the quantities used in the reaction reagents, the number of compounds [30] is from 1 to 20 equivalents per equivalent of the compound [29], and the amount of base is from 1 to 3 equivalents.

As the Foundation can be named, for example, carbonates of alkali metals such as sodium carbonate, potassium carbonate, etc.; hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, etc.; hydrides of alkali metals such as potassium hydride, sodium hydride, etc.; alkali metal alcoholate, such as ethoxide sodium methoxide, sodium, etc. and organic bases such as 1,8-diazabicyclo[5.4.0]-7-undecene etc.

The solvent can be named, for example, halogenated hydrocarbons such as dichloromethane, chloroform and so on; ethers such as diethyl ether, tetrahydrofuran and so on; aromatic hydrocarbons such as benzene, toluene and so on; aliphatic hydrocarbons such as hexane, heptane and so on; ketones such as acetone, methyl isobutyl ketone and so on; esters such as ethyl acetate, methyl acetate and so on; amides such as N-organic, N,N-dimethylformamide, etc.; sulfur compounds such as dimethylsulfoxide, and sulfolane so; NITRILES, such as acetonitrile, etc. and mixtures thereof.

Among the compounds represented by the General formula[4], [17], [18], [19], [20], [22], [23], [26], [29] or [31], the compound represented by the General fo what mulai [34], can be obtained in the following way.

In the above reaction L1has the same definition given above; the substituent R10represents an alkyl group, the alkyl group monosubstituted by a group selected from the group of substituents β, halogenation group, cycloalkyl group, alkenylphenol group, alkylamino group, alkylsulfonyl group, alkylsulfonyl group, alkylsulfonyl group monosubstituted by a group selected from the group of substituents γ, halogenated.sulphonated group optionally substituted phenyl group, optionally substituted aromatic heterocyclic group, optionally substituted phenylsulfonyl group, optionally substituted aromatic heterocyclic sulfonyloxy group, acyl group, halogencarbonic group, optionally substituted benzylcarbamoyl group, optionally substituted benzoyloxy group, alkoxycarbonyl group, optionally substituted benzyloxycarbonyloxy group, optionally substituted phenoxycarbonyl group or karbamoilnuyu group (its nitrogen atom may be substituted by identical or different groups selected from alkyl groups and optionally substituted phenyl group). Atoms coal is an ode to the pyrazol ring can be substituted by 1-2 are the same or different groups, selected from the group of substituents α.

The connection represented by the General formula [34], can be obtained by the reaction of compound [32] with the compound [33] in a solvent in the presence of a base.

This reaction is usually carried out at temperatures from 0 to 120°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, the amount of compound [33] is from 1 to 20 equivalents per equivalent of the compound [32], and the amount of base is from 1 to 3 equivalents.

As the base and solvent include, for example, the same bases and solvents, which are referred to when the connection [31] from the compound [29].

Introduction triptorelin group Y may be conducted under or pursuant to, for example, methods described in J. Chem. Soc. Perkin Trans., 1, 8, 2293-2299 (1990); J. Fluorine Chem., 50 (3), 411-426 (1990); J. Chem. Soc. Chem. Commun., 18, 1389-1391 (1993); J. Chem. Soc. Chem. Commun., 1, 53-54 (1992); Chem. Lett., 1719-1720 (1981); Chem. Pharm. Bull., 38 (9), 2446-2458 (1990); J. Chem. Soc. Perkin Trans., 1, 921-926 (1988); Heterocycles, 37 (2), 775-782 (1994); Tetrahedron Lett., 30 (16), 2133-2136 (1989); J. Chem. Soc. Perkin Trans., 1, 2755-2761 (1980); Heterocycles, 22 (1), 117-124 (1984); Eur. J. Med. Chem. Chim. Ther., 24, 249-258 (1989); Acta Chem. Scand. Ser. B, 38 (6), 505-508 (1984); J. Fluorine Chem., 21, 495-514 (1982); J. Chem. Soc. Chem. Commun., 10, 638-639 (1988); J. Fluorine Chem., 67 (1), 5-6 (1994); J. Heterocycl. Chem., 31 (6), 1413-1416 (1994); Chem. Heterocycl. Compd., 30 (5), 576-578 (1994); J. Fluorine Chem., 78 (2), 177-182 (1996); J. Heterocycl. Chem., 34 (2), 551-556 (1997); Tetrahedron, 55 (52), 15067-15070 (1999), the Synthesis, 11, 932-933 (1980).

Compounds represented by the General formula[4], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [29] or [31], can be obtained according to or based on, for example, the methods described in Methods der Organischen Chemie, EA, 16-185 (1994), when Y represents follow group; der Organischen Chemie Methods, EA, 186-555 (1994), when Y represents a thienyl group; der Organischen Chemie Methods, EA, 556-798 (1994), when Y represents pyrrolidino group; der Organischen Chemie Methods, 8b, 399-763 (1994) and JP-A-2000-219679, when Y represents pyrazolidine group; der Organischen Chemie Methods, EA, 45-225 (1993), when Y represents isoxazolyl group; der Organischen Chemie Methods, EA, 668-798 (1993), when Y represents isothiazolinone group; der Organischen Chemie Methods, EA, 891-1019 (1993), when Y represents oxazolidinyl group; der Organischen Chemie Methods, 8b, 1-398 (1994), when Y represents thiazolino group; der Organischen Chemie Methods, Es, 1-215 (1994), when Y represents imidazolidinyl group; der Organischen Chemie Methods, EA, 286-686 (1992), when Y represents pyridyloxy group; der Organischen Chemie Methods, EA, 557-682 (1997), when Y represents pyridazinyl group; der Organischen Chemie Methods, 9b/1, 1-249 (1998)when Y represents pyrimidinyl group; der Organischen Chemie Methods, 9b/1, 250-372 (1998), when Y represents personilnya group; der Organischen Chemie Methods, Es, 530-796 (1998), when Y represents triazinyl group Methods der Organischen Chemie, 8d, 305-405 and 479-598 (1994), when Y represents triazolyl group; der Organischen Chemie Methods, Es, 397-818 (1994), when Y represents oxadiazolyl group; der Organischen Chemie Methods, 8d, 59-305 (1994), when Y represents thiadiazolyl group; der Organischen Chemie Methods, 6b1, 33-216 (1994), and in International patent publication WO-1997/29105, when Y represents benzofuranyl group; der Organischen Chemie Methods, 6b1, 217-322 (1994), when Y represents a group benzothiazoline; Der Organischen Chemie methods, 6b1, 546-848 (1994), der Organischen Chemie Methods, 6b2, 849-1336 (1994), and in International patent publication WO-1997/42188-A1, when Y represents indolenine group; der Organischen Chemie Methods, EA, 1020-1194 (1993), when Y represents benzoxazolyl group; der Organischen Chemie Methods, 8b, 865-1062 (1994), when Y represents benzothiazolyl group; der Organischen Chemie Methods, Es, 216-391 (1994), when Y represents benzimidazolyl group; Methods der Organischen Chemie, EA, 226-348 (1993), when Y represents benzisoxazole group; der Organischen Chemie Methods, EA, 799-852 (1993), when Y represents benzisothiazolinone group; der Organischen Chemie Methods, 8b, 764-864 (1994), when Y represents indazolinone group; der Organischen Chemie Methods, EA, 290-570 (1991), when Y represents pinolillo group; der Organischen Chemie Methods, EA, 571-758 (1991), when Y represents izohinolinove group; Methods der Organischen Chemie, EA, 744-789 (1997), when Y is present which allows talinolol group; Methods der Organischen Chemie, 9b/2, 93-265 (1998), when Y represents khinoksalinona group; der Organischen Chemie Methods, 9b/2, 1-192 (1998), when Y represents chinazolinei group; der Organischen Chemie Methods, EA, 683-743 (1997), when Y represents indolinyl group, and Methods der Organischen Chemie, 8d, 406-478 (1994), when Y represents benzotriazolyl group.

<a Method of obtaining 2>

In the above reaction, the substituents R1, R2, R3, R4, R5and R6have the definitions given above. Carbon atoms pyrazol ring can be substituted by 1-2 are the same or different groups selected from the group of substituents α.

The compound of the present invention represented by the General formula [36], can be obtained by reaction of the compound [35] the present invention obtained by the method of obtaining 1, with an acid in a solvent.

This reaction is usually carried out at temperatures from 0 to 120°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, the amount of acid is from 1 to 10 equivalents per equivalent of the compound [35]; however, this number may vary accordingly depending on the reaction conditions.

The acid can be mentioned, for example, hydrochloric acid, Hydrobromic to the slot and triperoxonane acid.

The solvent can be named, for example, halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and so on; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone etc.; sulfur-containing compounds such as dimethylsulfoxide, sulfolan etc.; carboxylic acids such as formic acid, acetic acid, etc. and the water.

<a Method of obtaining 3>

In the above reaction, n, L1, R1, R2, R3, R4, R5, R6and R10have the definitions given above. Carbon atoms pyrazol ring can be substituted by 1-2 are the same or different groups selected from the group of substituents α.

The compound of the present invention represented by the General formula [37], can be obtained by reaction of the compound of the present invention [36] with the compound [33] in a solvent in the presence of a base.

As for the quantities used in the reaction of the reagents, the amount of compound [33] is from 1 to 3 equivalents per equivalent of the compound represented by the General formula [36], and the amount of base is from 1 to 3 equivalents.

As solvents can be named, for example, ethers such as dioxane, tetrahydrofuran (THF), and others; ha is generowanie hydrocarbons, such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and others; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone etc.; sulfur-containing compounds such as dimethylsulfoxide, sulfolane and so on; aromatic hydrocarbons such as benzene, toluene, xylene and so on; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol and so on; ketones such as acetone, 2-butanone, etc.; NITRILES, such as acetonitrile and so on; water, and mixtures thereof.

As grounds include, for example, metal hydrides such as sodium hydride and so on; amides of an alkali metal such as sodium amide, diisopropylamide lithium and so on; organic bases, such as pyridine, triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene etc.; hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, etc.; hydroxides of alkaline earth metals such as calcium hydroxide, magnesium hydroxide, etc.; carbonates of alkali metals such as sodium carbonate, potassium carbonate, etc.; bicarbonates of alkali metals, such as sodium bicarbonate, potassium bicarbonate, etc. and a metal alcoholate such as sodium methoxide, tert-piperonyl potassium, etc.

<a Method of obtaining 4>

In the above reaction, the substituents R1, R2, R3,R 4, R5and R6have the definitions given above; the substituent R11represents a hydrogen atom or a group of substituents αdescribed above; Deputy X3represents a chlorine atom, a fluorine atom, alkylsulfonyl group or optionally substituted benzylaniline group; the substituent R12represents an alkyl group, halogenation group, cycloalkyl group, cycloalkenyl group, alkenylphenol group, alkylamino group optionally substituted phenyl group, optionally substituted aromatic heterocyclic group, alkoxycarbonyl group, optionally substituted heterocyclic alkyl group or optionally substituted benzyl group; the substituent R13represents an alkyl group, halogenation group optionally substituted phenyl group, optionally substituted aromatic heterocyclic group, alkoxycarbonyl group or optionally substituted benzyl group; the substituents R14and R15may be the same or different and each represents a hydrogen atom, alkyl group, optionally substituted phenyl group, acyl group, halogencarbonic group, optionally substituted benzylcarbamoyl the ing group, optionally substituted benzoyloxy group, alkylsulfonyl group, halogenated.sulphonated group, optionally substituted benzylaniline group or optionally substituted phenylsulfonyl group, and Z represents an oxygen atom, a sulfur atom, N=CR11a, CR11a=N, CR11a=CR11bor N-R16(where the substituent R16represents a hydrogen atom or has the same meaning as the substituent R10and the substituents R11aand R11bhave the same meaning as R11).

Compounds of the present invention represented by the General formula [40], [42] and [44], can be obtained by reaction of the compound of the present invention represented by the General formula [38], with the compound [39], compound [41] and the compound [43], respectively, in the presence or in the absence of solvent and necessarily in the presence of a base.

This reaction is usually carried out at a temperature of from 20 to 200°C, preferably from 30 to 180°With over 10 min to 48 h, and optionally under pressure.

As for the quantities used in the reaction of the reagents, the amount of compound [39], connections [41] or the compound [43] is from 1 to 20 equivalents per equivalent of the compound [38].

Since the use of reason necessary, can be called, for example, hydroxides of alkali metals, such as g is droxia potassium, sodium hydroxide, etc.; hydrides of alkali metals such as potassium hydride, sodium hydride, etc.; alkali metal alcoholate, such as ethoxide sodium methoxide, sodium, etc. and organic bases such as 1,8-diazabicyclo[5.4.0]-7-undecene etc.

As solvents can be named, for example, halogenated hydrocarbons such as chloroform and others; ethers such as diethyl ether, tetrahydrofuran and others; aromatic hydrocarbons such as benzene, toluene and so on; aliphatic hydrocarbons such as hexane, heptane and so on; ketones such as acetone, methyl isobutyl ketone and so on; esters such as ethyl acetate and so on; amides such as N-organic, N,N-dimethylformamide, etc.; sulfur-containing compounds such as dimethylsulfoxide, sulfolan etc.; acetonitrile, as well as mixtures thereof.

<a Method of obtaining 5>

In the above reaction, the substituents R1, R2, R3, R4, R5, R6, R8, R11and Z have the same definitions given above.

The compound of the present invention represented by the General formula [46], can be obtained by the reaction of compound [45] of the present invention with an acid in a solvent.

This reaction is usually carried out at temperatures from 0 to 120°C for from 10 min to 24 hours.

H what about the concerns of the quantities used in the reaction reagents, the amount of acid is preferably from 1 to 10 equivalents per equivalent of the compound [45]; however, this number may vary accordingly depending on the reaction conditions.

The acid and solvent can be called the same acids and solvents, which was mentioned in the production method of 2.

<a Method of obtaining 6>

In the above reaction, the substituents Y, R1, R2, R3, R4, R5, R6, R9and L1have the same definitions given above. Y may be substituted by 1-5 identical or different groups selected from the group of substituents α.

The connection represented by the General formula [48], in accordance with the present invention can be obtained by the reaction of compound [47] of the present invention with the compound [30] in a solvent in the presence of a base.

This reaction is usually carried out at temperatures from 0 to 150°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, the amount of acid is preferably from 1 to 1.2 equivalents per equivalent of the compound [47]; however, this number may vary accordingly depending on the reaction conditions.

As the base and solvent can be called the same bases and solvents, to the categories mentioned in the method of obtaining 3.

<a Method of obtaining 7>

In the above reaction, the substituents Y, R1, R2, R3, R4, R5and R6have the same definitions given above, and the substituent R17represents an alkyl group, optionally substituted benzyl group or an optionally substituted phenyl group. Y may be substituted by 1-5 identical or different groups selected from the group of substituents α.

The connection represented by the General formula [50], in accordance with the present invention can be obtained by hydrolysis of compound [49] the present invention in water or in a mixed solvent of water and another solvent in the presence or in the absence of base.

This reaction is usually carried out at temperatures from 0 to 100°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, the amount of the base, if used, is preferably from 1 to 2 equivalents per equivalent of the compound [49]; however, this number may vary accordingly depending on the reaction conditions.

As grounds include, for example, inorganic bases such as potassium carbonate, sodium hydride, sodium hydroxide, etc. and organic bases such as 1,8-diazabicyclo[5.4.0]-7-undeca and so on

As another solvent, mixed with water, can be called, for example, alcohols such as methanol, ethanol and so on; ethers such as tetrahydrofuran and so on; ketones such as acetone, methyl isobutyl ketone and so on; amides such as N,N-dimethylformamide, etc.; sulfur-containing compounds such as dimethylsulfoxide, sulfolan etc.; acetonitrile, and mixtures thereof.

<a Method of obtaining 8>

In the above reaction, the substituents Y, R1, R2, R3, R4, R5, R6and R8have the same definitions given above, and the substituent R18represents an alkyl group. Y may be substituted by 1-5 identical or different groups selected from the group of substituents α.

The connection represented by the General formula [53], in accordance with the present invention can be obtained by reaction of the compound [51] of the present invention with the compound [52] in a solvent in the presence of a base.

This reaction is usually carried out at temperatures from 0 to 100°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, the amount of the hydrochloride or sulfate compounds [52] is preferably from 1 to 5 equivalents per equivalent of the compound [51], and the amount of base is preferably from 1 to 10 equivalents; one is to this number may vary accordingly depending on the reaction conditions.

As grounds include, for example, metal carbonates such as potassium carbonate, sodium carbonate, etc.; acetates of metals, such as potassium acetate, sodium acetate, etc. and organic bases such as triethylamine, dimethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene etc.

The solvent includes, for example, alcohols such as methanol, ethanol and so on; ethers such as tetrahydrofuran and so on; amides such as N,N-dimethylformamide, etc. and mixtures thereof.

<a Method of obtaining 9>

In the above reaction, the substituents Y, R1, R2, R3, R4, R5and R6have the same definitions given above; and each of the substituents R19and R20represents a hydrogen atom or alkyl group. Y may be substituted by 1-5 identical or different groups selected from the group of substituents α.

The connection represented by the General formula [57], in accordance with the present invention can be obtained by reaction of the compound [50] of the present invention with thionyl chloride in the presence or in the absence of a solvent to obtain the compound [55], and then by reaction of the compound [55] with the compound [56] in the presence or in the absence of solvent.

The reaction from the compound [50] to the compound [55] is usually carried out at a temperature of from 0 to 10° C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, the amount of thionyl chloride [54] is preferably from 1 to 100 equivalents per equivalent of the compound [50], but it can be modified appropriately depending on the reaction conditions.

The solvent includes, for example, halogenated hydrocarbons such as dichloromethane, chloroform and so on; ethers such as diethyl ether, tetrahydrofuran, etc. and aromatic hydrocarbons such as benzene, toluene, etc.

The reaction from the compound [55] to the compound [57] is usually carried out at temperatures from 0 to 100°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, the amount of compound [56] is preferably from 1 to 100 equivalents per equivalent of the compound [55], but it can be modified appropriately depending on the reaction conditions.

The solvent includes, for example, the same solvents used in the reaction from the compound [50] to the compound [55].

<a Method of obtaining 10>

In the above reaction, the substituents Z, R1, R2, R3, R4, R5, R6, R11and X3have the same definitions given above.

The connection represented by the General forms of the Loy [59], in accordance with the present invention can be obtained by reaction of the compound [38] of the present invention with the compound [58] in a solvent.

This reaction is usually carried out at temperatures from 0 to 100°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, the amount of compound [58] is preferably from 1 to 2 equivalents per equivalent of the compound [38], but it can be modified appropriately depending on the reaction conditions.

The solvent includes, for example, ethers such as dioxane, tetrahydrofuran (THF), etc.; halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and others; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone etc.; sulfur-containing compounds such as dimethylsulfoxide, sulfolane and so on; ketones such as acetone, 2-butanone, etc.; NITRILES, such as acetonitrile, etc.; water; and their of the mixture.

<a Method of obtaining 11>

In the above reaction, the substituents Y, R1, R2, R3, R4, R5and R6have the same definitions given above, and the substituent R21represents an alkyl group, halogenation group, cycloalkyl group, cycloalkenyl group, and kenelog group, alkylamino group, alkoxycarbonyl group, optionally substituted heteroalkyl group or optionally substituted benzyl group. Y may be substituted by 1-5 identical or different groups selected from the group of substituents α.

The connection represented by the General formula [61], in accordance with the present invention can be obtained by reaction of the compound of the present invention [47] with the compound [60] in the presence of azo compounds and triphenylphosphine in a solvent in accordance with the known method [Synthesis, 1-28 (1981)].

This reaction is usually carried out at temperatures from 0 to 100°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, the amount of compound [60], azo compounds and triphenylphosphine are preferably from 1 to 1.5 equivalents per equivalent of the compound [47], but these quantities may vary accordingly depending on the reaction conditions.

The solvent includes, for example, ethers such as dioxane, tetrahydrofuran (THF), etc.; halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, dichlorobenzene and others; amides such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone etc.; sulfur-containing compounds such as dimethylsulfoxide, sulfolan etc.; aromatic the ski hydrocarbons, such as benzene, toluene, xylene and so on; acetonitrile, and mixtures thereof.

As the azo compounds include, for example, diethylazodicarboxylate and diisopropylsalicylic.

<a Method of obtaining 12>

In the above reaction, the substituents X3, n, R1, R2, R3, R4, R5, R6and Z have the same definitions given above, and m takes integer values from 1 to 4. The carbon atom at the 3-position of the pyrazol ring may be substituted by a group selected from the group of substituents α.

The connection represented by the General formula [63], in accordance with the present invention can be obtained by reaction of the compound of the present invention [62] in the presence of a base in a solvent.

This reaction is usually carried out at temperatures from 0 to 120°C for from 10 min to 24 hours.

As for the quantities used in the reaction of the reagents, the amount of base is preferably from 1 to 3 equivalents per equivalent of compound [62], but this number may vary accordingly depending on the reaction conditions.

As the base and solvent can be named the same bases and solvents that were mentioned in the method of obtaining 3.

In addition, the sulfide compound referred to in the method of obtaining 2 and is and the ways to get 4-11, can be turned into sulfoxide connection or sulfonic compound by oxidation in accordance with the method described in the method of obtaining 1. In addition, the sulfide compound referred to in the method of obtaining 2 or ways to get 4-11, in which Deputy Y substituted C1-C10-alkylthiol, C1-C10-alkylthiophene, monosubstituted by a group selected from the group of substituents γor C1-C4-garagentore, can be turned into sulfoxide connection or sulfonic connection in accordance with the method described in production method of 1, by adding from an equimolar amount to an excess of oxidizing agent to the sulfide compound; with simultaneous oxidation of the Deputy, substitute Deputy Y (C1-C10-allylthiourea, C1-C10-allylthiourea, monosubstituted by a group selected from the group of substituents γor C1-C4-halogenlampe), and the conversion of this Deputy in sulfoxide group or sulfonic group.

Next, using examples, the specific description of the method of obtaining the compounds of the present invention, the method of obtaining the considered herbicide and method of use of the herbicide. Also describes the method of obtaining each intermediate compounds of the present invention.

<Example 1>

Obtain 3-(5-chloro-1-phenyl-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0001)

To a solution of 2.3 g (of 13.1 mmol) of 5,5-dimethyl-3-methylsulphonyl-2-isoxazoline in 20 ml of N,N-dimethylformamide added 2.1 g of the hydrate of sodium hydrosulfide (purity 70%, to 26.2 mmol). The mixture is stirred for 2 hours. To the mixture is added 1.8 g (of 13.1 mmol) of anhydrous potassium carbonate, 2.0 g (of 13.1 mmol) rongalite and 3.6 g (10.5 mmol) of 4-methyl bromide-5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 15 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), to obtain 2.7 g (yield 65,5%) of 3-(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in the form of white crystals (melting point 89-90°).

1H-NMR [DCl3/TMS δ (ppm)]: 7,55 is 7.50 (5H, m)to 4.33 (2H, s), and 2.83 (2H, s)to 1.45 (2H, s).

<Example 2>

Obtain 3-(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0002)

To a solution of 0.4 g (1.0 mmol) 3-(5-chloro-1-phenyl-3-reformer-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline, dissolved in 15 ml of chloroform, add 0,63 g m-chlormadinone acid (purity 70%, 2.6 mmol) under cooling with ice. The mixture is stirred at room temperature for 22 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The resulting crystals are washed with hexane, to obtain 0.4 g (yield: 83,2%) of 3-(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline in the form of white crystals (melting point 132-133°).

1H-NMR [DCl3/TMS δ (ppm)]: 7,60-7,51 (5H, m), 4,37 (2H, s), 3,14 (2H, s)of 1.53 (2H, s).

<Example 3>

Obtain 3-(5-chloro-1-methyl-3-phenyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0003)

To a solution of 0.85 g (2,53 mmol) 3-(5-chloro-1-methyl-3-phenyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in 30 ml of chloroform added 0.87 g m-chlormadinone acid (purity 70%, 3.54 mmol) under cooling with ice. The mixture is stirred at room temperature for 1 hour to about what Cania reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), gain of 0.48 g (yield 53,9%) of 3-(5-chloro-1-methyl-3-phenyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline in the form of a transparent viscous substance.

1H-NMR [DCl3/TMS δ (ppm)]: 7,63-of 7.60 (2H, m), of 7.48-7,37 (3H, m), the 4.29 (2H, q), 3,91 (3H, s), 3,12 (1H, d), and 2.79 (1H, d), of 1.41 (3H, s)of 1.35 (3H, s).

<4>

Getting 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline (compound of the present invention No. 3-0021)

To a solution of 18.7 g (105,7 mmol) of 5,5-dimethyl-3-methylsulphonyl-2-isoxazoline (compound of the invention No. 2-1) in 300 ml of N,N-dimethylformamide added 9.3 g of the hydrate of sodium hydrosulfide (purity 70%, 116,3 mmol). The mixture is stirred for 2 hours. The reaction system is cooled with ice. To the mixture add a solution of 30.3 g (93,8 mmol) 4-methyl bromide-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole in 200 ml of N,N-dimetilformamida. The mixture was stirred at 0°C for 30 min for the reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), get 13,11 g (yield 37,4%) of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline in the form of a yellow oily substance.

1H-NMR [DCl3/TMS δ (ppm)]: the 7.65 7,39 (5H, m), 4,24 (2H, s), of 2.81 (2H, s), 1,43 (6N, C).

<Example 5>

Getting 5,5-dimethyl-3-(5-ethylthio-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline (compound of the present invention No. 3-0022)

To a solution of 0.25 g (4.0 mmol) of ethanthiol in 10 ml of N,N-dimethylformamide added 0.2 g (4.0 mmol) of sodium hydroxide and 1 ml of water. The mixture is stirred at room temperature for 30 minutes To the mixture add a solution of 0.5 g (1.4 mmol) of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline in 5 ml of N,N-dimethylformamide. The resulting mixture was stirred for 1 hour for reaction. Upon completion of the reaction, the reaction mixture is then poured the water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 0.6 g (yield 100%) of 5,5-dimethyl-3-(5-ethylthio-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline.

1H-NMR [DCl3/TMS δ (ppm)]: 7,62-7,47 (5H, m), of 4.44 (2H, s), and 2.83 (2H, s)of 2.50 (2H, HF), 1,45 (6N, C)of 1.02 (3H, t).

<Example 6>

Getting 5,5-dimethyl-3-(5-ethylsulfonyl-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-2-isoxazoline (compound of the present invention No. 3-0004)

To a solution of 0.6 g (1.3 mmol) of 5,5-dimethyl-3-(5-ethylthio-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline in 10 ml of chloroform added 1.7 g m-chlormadinone acid (purity 70%, 6.7 mmol) under cooling with ice. The mixture is stirred at room temperature for 16 h reaction time. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove codereaders is it solvent. The resulting crystals are washed with hexane, to obtain 0.6 g (yield 93,0%) of 5,5-dimethyl-3-(5-ethylsulfonyl-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-2-isoxazoline in the form of light yellow crystals (melting point 158-160°).

1H-NMR [DCl3/TMS δ (ppm)]: 7,58-rate of 7.54 (5H, m), 5,16 (2H, s)3,18 (2N, C)and 3.15 (2H, HF), 1.55V (6N, C)of 1.24 (3H, t).

<Example 7>

Getting 5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline (compound of the present invention No. 3-0023)

To a solution of 0.5 g (1.3 mmol) of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide added 0.8 g (6.7 mmol) of a 40%aqueous solution of dimethylamine. The mixture is stirred in a sealed tube at 100°C for 9 hours. To a mixture of 3.0 g (to 26.6 mmol) of a 40%aqueous solution of dimethylamine and the mixture was stirred for 9 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed dissolve Italy hexane-ethyl acetate), obtain 0.4 g (yield of 80.6%) of 5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline.

1H-NMR [DCl3/TMS δ (ppm)]: 7,58-7,38 (5H, m), 4,35 (2H, s), 2,82 (2H, s), 2,77 (6N, (C), 1,45 (6N, C).

<Example 8>

Getting 5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-2-isoxazoline (compound of the present invention No. 3-0005)

To a solution of 0.4 g (1.1 mmol) of 5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline in 10 ml of chloroform, add 0.7 g m-chlormadinone acid (purity 70%, 2.7 mmol) under cooling with ice. The mixture is stirred at room temperature for 20 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The resulting crystals are washed with hexane, to obtain 0.2 g (yield 52,0%) of 5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-2-isoxazoline in the form of a white powder (melting point 150-151°).

1H-NMR [Dl 3/TMS δ (ppm)]: to 7.61-7,38 (5H, m), and 4.75 (2H, s), 3,13 (2H, s), was 2.76 (6N, C)1,53 (6N, C).

<Example 9>

Obtaining 3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0006)

To a solution 24,1 g (136,0 mmol) of 5,5-dimethyl-3-methylsulphonyl-2-isoxazoline in 200 ml of N,N-dimethylformamide added 21.8 g of sodium hydrosulfide (purity 70%, 272,5 mmol). The mixture is stirred for 1 hour. To the mixture of 18.8 g (136,2 mmol) of anhydrous potassium carbonate and 21.0 g (136,2 mmol) rongalite. The resulting mixture was stirred for 2 hours. To the mixture while cooling with ice, add 40 g (125 mmol) of 4-methyl bromide-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 2 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), get 23,0 g (yield of 57.1%) 3-(1-tert.-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline as light pink crystals (temperature PL is the exercise: 79,0-81,0° C).

1H-NMR [DCl3/TMS δ (ppm)]: 4,24 (2H, s), 2,80 (2H, s), 1,71 (N, C)1,43 (6N, C).

<Example 10>

Obtain 3-(5-chloro-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0007)

Add to 19.8 g (53,4 mmol) 3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline to 170 ml of a 25%solution of hydrogen bromide/acetic acid. The resulting mixture was stirred at 40-50°C for 2 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 12.0 g (yield 60,6%) of 3-(5-chloro-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in the form of light yellow crystals (melting point: 120,0-122,0°).

1H-NMR [DCl3/TMS δ (ppm)]: 4.26 deaths (2H, s), of 2.81 (2H, s), 1,44 (6N, C).

<Example 11>

Obtain 3-(5-chloro-1-deformity-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0008) and 3-(3-chloro-1-deformity-5-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline (joint the present invention No. 3-0009)

To a solution of 2.3 g (7.3 mmol) of 3-(5-chloro-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in 50 ml of N,N-dimethylformamide added 3.1 g (to 22.5 mmol) of anhydrous potassium carbonate. The mixture is rinsed with Chlorodifluoromethane. The resulting mixture was stirred at 130-140°3 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), get to 0.69 g (yield of 25.8%) of 3-(5-chloro-1-deformity-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in the form of light yellow crystals (melting point 41,0-42,0° (C) and 0.54 g (yield 20,2%) of 3-(3-chloro-1-deformity-5-trifluoromethyl-1H-pyrazole-4 immedilty)-5,5-dimethyl-2-isoxazoline in the form of a white powder (melting point 89,0-90,0°).

3-(5-chloro-1-deformity-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline

1H-NMR [DCl3/TMS δ (ppm)]: 7,22 (1H, t), 4,25 (2H, s), 2,80 (2H, s), 0,44 (6N, C).

3-(3-chloro-1-deformity-5-trifluoromethyl-1H-pee the azole-4-immedilty)-5,5-dimethyl-2-isoxazoline

1H-NMR [DCl3/TMS δ (ppm)]: 7,19 (1H, t), 4,28 (2H, s), 2,80 (2H, s), 1,44 (6N, C).

<Example 12>

Obtain 3-(5-chloro-1-deformity-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0010)

To a solution 0,69 g (1.9 mmol) of 3-(5-chloro-1-deformity-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline in 20 ml of chloroform added 1.4 g m-chlormadinone acid (purity 70%, 8.1 mmol) under cooling with ice. The mixture is stirred for 1 hour, and then 12 h at room temperature for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The obtained solid is washed with n-hexane, to obtain 0.4 g (yield 53,3%) of 3-(5-chloro-1-deformity-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline in the form of a white powder (melting point 126,0-127,0°).

1H-NMR [DCl3/TMS δ (ppm)]: 7,26 (1H, t), and 4.68 (2H, s), 3,11 (2H, s), 1,53 (6N, C).

<Example 13>

Getting 3(3-chloro-1-deformity-5-trifluoromethyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0011)

To a solution of 0.54 g (1.5 mmol) of 3-(3-chloro-1-deformity-5-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in 20 ml of chloroform added 1.1 g m-chlormadinone acid (purity 70%, 6.4 mmol) under cooling with ice. The mixture is stirred for 1 hour and then at room temperature for 12 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The obtained solid is washed with n-hexane, get to 0.47 g (yield 79,7%) of 3-(3-chloro-1-deformity-5-trifluoromethyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline in the form of a white powder (melting point 136,0-137,0°).

1H-NMR [DCl3/TMS δ (ppm)]: of 7.23 (1H, t), 4,71 (2H, s), 3,11 (2H, s), 1,53 (6N, C).

<14>

Getting 5,5-dimethyl-3-(3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline (compound of the present invention No. 3-0024)

To a solution of 3.3 g (17.3 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 10 ml of N,N-dimethylformamide added 3.1 g is igrata sodium hydrogen sulfide (purity 70%, to 22.0 mmol). The mixture is stirred for 2 hours. To the mixture of 3.1 g (22,0 mmol) of anhydrous potassium carbonate, 2.7 g (17.5 mmol) of rongalit and 4.0 g (17.5 mmol) 4-chloromethyl-3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 2 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), to obtain 2.8 g (yield 52,0%) of 5,5-dimethyl-3-(3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline.

<Example 15>

Getting 5,5-dimethyl-3-(3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline (compound of the present invention No. 3-0025)

To 20 ml of 25%solution of hydrogen bromide in acetic acid is added to 3.3 g (10.6 mmol) of 5,5-dimethyl-3-(3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline. The mixture was stirred at 50°3 hours for reaction. Upon completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the contained solvent is. The residue poured into water. The resulting crystals are filtered, washed with water and dried, to obtain 3.1 g (yield 96,0%) target 5,5-dimethyl-3-(3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline.

<Example 16>

Getting 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline (compound of the present invention No. 3-0026)

To a solution of 0.30 g (1.0 mmol) of 5,5-dimethyl-3-(3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline in 10 ml of N,N-dimethylforamide add 0.20 g (1.3 mmol) of anhydrous potassium carbonate and 0.20 g (1.5 mmol) of ethyliodide. The mixture was stirred at 50°3 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent gain of 0.30 g (yield 92,0%) named 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline.

<Example 17>

Getting 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazole-4-elmersolver)-2-isoxazoline (compound of the present invention No. 3-0012)

To a solution of 0.30 g (0,92 mmol) of 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazole-4-and the methylthio)-2-isoxazoline in 10 ml of chloroform added to 0.68 g m-chlormadinone acid (purity 70%, was 2.76 mmol) under cooling with ice. The mixture is stirred at room temperature for 5 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The resulting crystals are washed with hexane, to obtain 0.24 g (yield 73,0%) of 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazole-4-elmersolver)-2-isoxazoline in the form of white crystals (melting point 124-125°).

1H-NMR [DCl3/TMS δ (ppm)]: 4,50 (2H, s), 4,27 (2H, HF), 3,86 (3H, s), 3.04 from (2H, s), 1,49 (6N, C)of 1.39 (3H, t).

<Example 18>

Getting 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline (compound of the present invention No. 3-0027)

To a solution of 21.3 g (to 120.3 mmol) of 5,5-dimethyl-3-methylsulphonyl-2-isoxazoline in 200 ml of N,N-dimethylformamide add 19.3 g of sodium hydrosulfide (purity 70%, 344,6 mmol). The mixture is stirred for 1 hour. To a mixture of 16.7 g (to 121.0 mmol) of anhydrous potassium carbonate and 18.6 g (of 120.7 mmol) rongalite. The resulting mixture was stirred for 2 hours. To the mixture while cooling the ice type of 31.4 g (of 102.3 mmol) 4-methyl bromide-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 2 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 29.0 g (yield of 90.3%) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline in the form of a yellow oily substance.

1H-NMR [DCl3/TMS δ (ppm)]: 4,24 (2H, s), 3,90 (3H, s), 2,78 (2H, s), 1,42 (6N, C).

<Example 19>

Getting 5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline (compound of the present invention No. 3-0028)

To a solution of 0.5 g (1.6 mmol) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline in 20 ml of methanol add 0,77 g (4.0 mmol) of sodium methoxide (28%methanol solution). The mixture is stirred for 2 hours at the boil under reflux for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous is a Ulfat magnesium. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 0.5 g (yield 96,7%) of 5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline in the form of a yellow oily substance.

1H-NMR [DCl3/TMS δ (ppm)]: 4.26 deaths (2H, s)4,07 (3H, s), and 3.72 (3H, s), 2,80 (2H, s), 1,43 (6N, C).

<Example 20>

Getting 5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-2-isoxazoline (compound of the present invention No. 3-0013)

To a solution of 0.5 g (1.5 mmol) of 5,5-dimethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline in 20 ml of chloroform, add 1.3 g m-chlormadinone acid (purity 70%, 7.5 mmol) under cooling with ice. The mixture is stirred for 1 hour and then at room temperature for 12 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The obtained solid is washed with n-hexane, to obtain 0.31 g (yield 58.2 per cent) of 5,5-di is ethyl-3-(5-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole-4-elmersolver)-2-isoxazoline in the form of a white powder (melting temperature level 113.0-114,0° C).

1H-NMR [DCl3/TMS δ (ppm)]: 4,60 (2H, s), 4,11 (3H, s), with 3.79 (3H, s), 3,10 (2H, s)and 1.51 (6N, C).

<Example 21>

Obtain 3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0029)

To a solution of 0.44 g (3.4 mmol) of 2-chlorophenol in 30 ml of N,N-dimethylformamide added 0.2 g (8.3 mmol) of sodium hydride (purity 60%) while cooling with ice. The mixture is stirred for 1 hour. To the mixture of 0.7 g (2.2 mmol) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline. The resulting mixture was stirred at 120-130°C for 5 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane - ethyl acetate), get to 0.63 g (yield of 66.7%) 3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in the form of a yellow oily substance.

<Example 22>

Obtain 3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-piraso the-4-elmersolver)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0014)

To the solution was 0.63 g (1.5 mmol) of 3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in 20 ml of chloroform, add 1.0 g m-chlormadinone acid (purity 70%, 5.8 mmol) under cooling with ice. The mixture is stirred for 1 hour and then at room temperature for 12 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The obtained solid is washed with n-hexane, to obtain 0.31 g (yield of 45.7%) of 3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline in the form of a white powder (melting point 67,0-70,0°).

1H-NMR [DCl3/TMS δ (ppm)]: 7,50-6,91 (4H, m), of 4.45 (2H, s), 3,71 (3H, s), 3,03 (2H, s), 1,47 (6N, C).

<Example 23>

Obtain 3-(5-cyclopentyloxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0030)

To a solution of 0.43 g (1.6 mmol) of triphenylphosphine in 10 ml of benzene added 0.14 g (1.6 mmol) is of clobetasol, 0.5 g (1.6 mmol) of 5,5-dimethyl-3-(5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazol and 0.7 g (1.6 mmol) of diethylazodicarboxylate (40%toluene solution). The mixture is stirred at room temperature for 12 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane - ethyl acetate), to obtain 0.52 g (yield of 85.2%) of 3-(5-cyclopentyloxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in the form of a colorless transparent oily substance.

<Example 24>

Obtain 3-(5-cyclopentyloxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0015)

To a solution of 0.52 g (1.4 mmol) of 3-(5-(cyclopentyloxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in 20 ml of chloroform, add 0,85 g m-chlormadinone acid (purity 70%, 4.9 mmol) under cooling with ice. The mixture is stirred for 1 hour and then when the room is Noah temperature 12 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The obtained solid is washed with n-hexane, to obtain 0.2 g (yield of 35.5%) of 3-(5-(cyclopentyloxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline in the form of a white powder (melting temperature level 113.0-114,0°).

1H-NMR [DCl3/TMS δ (ppm)]: to 5.03 (1H, ush.), 4,60 (2H, s), of 3.73 (3H, s), 3,05 (2H, s), 1,88 is 1.70 (8H, m), 1,50 (6N, C).

<Example 25>

Obtain 3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0031)

To a solution of 0.5 g (1.6 mmol) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-2-isoxazoline in 30 ml of N,N-dimethylformamide added 0.2 g (4.0 mmol) of sodium cyanide. The mixture was stirred at 40°C for 1 hour for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer PR is myauth water and aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 0.9 g of crude 3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in the form of a yellow oily substance.

1H-NMR [DCl3/TMS δ (ppm)]: 4,30 (3H, s)4,08 (3H, s), of 2.81 (2H, s), 1,43 (6N, C).

<Example 26>

Obtain 3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0016)

To a solution of 0.9 g of 3-(5-cyano-1-methyl-3-trifluoromethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline (raw connection) in 50 ml of chloroform added 2.1 g m-chlormadinone acid (purity 70%, 12.2 mmol) under cooling with ice. The mixture is stirred for 1 hour and then at room temperature for 12 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The obtained solid is washed with n-hexane, gain of 0.43 g (yield of 76.4%) of 3-(5-cyano-1-m is l-3-trifluoromethyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline in the form of a white powder (melting point 105,0-108,0° C).

1H-NMR [DCl3/TMS δ (ppm)]: to 4.73 (2H, s)to 4.16 (3H, s), 3,14 (2H, s), 1,53 (6N, C).

<Example 27>

Obtaining 3-(3,5-dichloro-1-ethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0032)

To a solution of 0.7 g (3.7 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 30 ml of N,N-dimethylformamide add 0.6 g of sodium hydrosulfide (purity 70%and 10.7 mmol). The mixture is stirred for 1 hour. To the mixture of 0.51 g (3.7 mmol) of anhydrous potassium carbonate and 0.56 g (3.6 mmol) of rongalite. The resulting mixture was stirred for 2 hours. To the mixture while cooling with ice add 0.9 g (3.5 mmol) of 4-methyl bromide-3,5-dichloro-1-ethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 2 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane - ethyl acetate), to obtain 0.8 g (yield of 70.8%) of 3-(3,5-dichloro-1-ethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in the form of a colorless transparent oily substance is.

1H-NMR [DCl3/TMS δ (ppm)]: 4,14 (2H, s), 4,14 (2H, q), of 2.81 (2H, s), 1,43 (6N, C)of 1.42 (3H, t).

<Example 28>

Obtaining 3-(3,5-dichloro-1-ethyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0017)

To a solution of 0.8 g (2.6 mmol) of 3-(3,5-dichloro-1-ethyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in 20 ml of chloroform, add 2.0 g m-chlormadinone acid (purity 70%, 11.6 mmol) under cooling with ice. The mixture is stirred for 1 hour and then at room temperature for 12 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The obtained solid is washed with n-hexane, gain of 0.41 g (yield 46.6%) of 3-(3,5-dichloro-1-ethyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline in the form of a white powder (melting point 105,0-107,0°).

1H-NMR [DCl3/TMS δ (ppm)]: 4,48 (2H, s), 4,19 (2H, HF), 3,05 (2H, s)and 1.51 (6N, (C)a 1.45 (3H, t).

<Example 29>

Obtain 3-(5-chloro-3-deformity-1-methyln-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0020)

To a solution of 1.9 g (10.0 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 30 ml of N,N-dimethylformamide add 1.2 g of the hydrate of sodium hydrosulfide (purity 70%, 15.0 mmol). The mixture is stirred for 2 hours. To a mixture of 2.1 g (15.0 mmol) of anhydrous potassium carbonate, 2.3 g (15.0 mmol) of rongalit and 2.6 g (10.0 mmol) 4-methyl bromide-5-chloro-3-deformity-1-methyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 15 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane - ethyl acetate), to obtain 2.1 g (yield 68,0%) of 3-(5-chloro-3-deformity-1-methyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in the form of a colorless viscous liquid (n20D= 1,5183).

1H-NMR [DCl3/TMS δ (ppm)]: 6,70 (1H, t, J=54,2 Hz), 4,24 (2H, s), 3,86 (3H, s), 2,80 (2H, s), 1,42 (6N, C).

<30>

Obtain 3-(5-chloro-3-deformity-1-methyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 3-0018)

To a solution of 1.8 g (5.8 mmol) 3-5-chloro-3-deformity-1-methyl-1H-pyrazole-4-immedilty)-5,5-dimethyl-2-isoxazoline in 15 ml of chloroform added 3.6 g m-chlormadinone acid (purity 70%, 14.5 mmol) under cooling with ice. The mixture is stirred at room temperature for 22 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The resulting crystals are washed with hexane, to obtain 1.7 g (yield 85,9%) of 3-(5-chloro-3-deformity-1-methyl-1H-pyrazole-4-elmersolver)-5,5-dimethyl-2-isoxazoline in the form of white crystals (melting point 78-79°).

1H-NMR [DCl3/TMS δ (ppm)]: to 6.80 (1H, t, J=54,8 Hz), 4,60 (2H, s), 3,91 (3H, s), is 3.08 (2H, s)and 1.51 (6N, C).

<Example 31>

Getting 5,5-dimethyl-3-(5-methyl-3-cryptometrics-4-immedilty)-2-isoxazoline (compound of the present invention No. 4-0003)

To a solution of 0.4 g (2.3 mmol) of 5,5-dimethyl-3-methylsulphonyl-2-isoxazoline in 10 ml of N,N-dimethylformamide add 0.4 g of the hydrate of sodium hydrosulfide (purity 70%, 4.6 mmol). The mixture is stirred for 2 hours. To the mixture is added 0.3 g (2.3 mmol) of potassium carbonate, 0.4 g (2.3 mmol) of rongalit and 0.5 g (1.8 mmol) of 4-methyl bromide-5-methyl-3-cryptomaterial. The resulting mixture is displaced is more at room temperature for 14 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane - ethyl acetate), to obtain 0.4 g (yield: 70,0%) of 5,5-dimethyl-3-(5-methyl-3-cryptometrics-4-immedilty)-2-isoxazoline.

1H-NMR [DCl3/TMS δ (ppm)]: 4,11 (2H, s), 2,77 (2H, s)to 2.54 (3H, s), 1,42 (6N, C).

<Example 32>

Getting 5,5-dimethyl-3-(5-methyl-3-cryptometrics-4-elmersolver)-2-isoxazoline (compound of the present invention No. 4-0001)

To a solution of 0.4 g (1.3 mmol) of 5,5-dimethyl-3-(5-methyl-3-cryptometrics-4-immedilty)-2-isoxazoline in 10 ml of chloroform, add 0.8 g m-chlormadinone acid (purity 70%, 3.2 mmol) under cooling with ice. The mixture is stirred at room temperature for 4 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride in the specified by adke and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The resulting crystals are washed with hexane, to obtain 0.4 g (yield 95,0%) of 5,5-dimethyl-3-(5-methyl-3-cryptometrics-4-elmersolver)-2-isoxazoline in the form of white crystals (melting point 135-136°).

1H-NMR [DCl3/TMS δ (ppm)]: of 4.54 (2H, s), 3,11 (2H, s), 2,61 (3H, s), 1,52 (6N, C).

<Example 33>

Getting [(5-chloro-3-metalization-4-yl)methylthio]-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 4-0004)

To a solution of 0.89 g (5.00 mmol) of 5,5-dimethyl-3-methylsulphonyl-2-isoxazoline in 10 ml of N,N-dimethylformamide added at room temperature of 0.82 g of sodium hydrosulfide (purity 70%, at 10.00 mmol). The mixture is stirred for 2 hours. To this mixture 0,70 g (5.00 mmol) of anhydrous potassium carbonate, 0,78 g (5.00 mmol) rongalite and of 0.91 g (5.00 mmol) of 5-chloro-4-chloromethyl-3-methylisothiazolone. The resulting mixture was stirred at room temperature overnight for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The remainder of the sight of the with column chromatography on silica gel, get to 1.38 g (yield quantitative) [(5-chloro-3-metalization-4-yl)methylthio]-5,5-dimethyl-2-isoxazoline.

<Example 34>

Getting [(5-chloro-3-metalization-4-yl)methylsulphonyl]-5,5-dimethyl-2-isoxazoline (compound of the present invention No. 4-0002)

To a solution of 1.38 g (5.00 mmol) of [(5-chloro-3-metalization-4-yl)methylthio]-5,5-dimethyl-2-isoxazoline in 20 ml of chloroform, add 2,96 g m-chlormadinone acid (purity 70%, 12,00 mmol) under cooling with ice. The mixture is stirred for 1 hour and then at room temperature overnight for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The resulting residue is purified column chromatography on silica gel, to obtain 0.65 g (yield of 47.0%) [(5-chloro-3-metalization-4-yl)methylsulphonyl]-5,5-dimethyl-2-isoxazoline in the form of a yellow powder (melting point 113-114°).

1H-NMR [DCl3/TMS δ (ppm)]: 8,89 (1H, s), of 4.67 (2H, s), 3,05 (2H, s)at 2.59 (3H, s)and 1.51 (6N, C).

<Example 35>

Getting 5,5-dimethyl-3-[2,5-dime the Il-4-(1-methoxyaminomethyl)thiophene-3-immedilty]-2-isoxazoline (compound of the present invention No. 2-0002)

To a solution of 1.0 g (3.4 mmol) of 3-(4-acetyl-2,5-dimethylthiophene-3-immedilty)-5,5-dimethyl-2-isoxazoline in 50 ml ethanol add 0,57 g (6.8 mmol) of the hydrochloride of O-methylhydroxylamine and 0.56 g (6.8 mmol) of sodium acetate. The resulting mixture was stirred for 5 hours at the boil under reflux for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane - ethyl acetate), to obtain 0.4 g (yield of 36.4%) of 5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyaminomethyl)thiophene-3-immedilty]-2-isoxazoline in the form of a yellow oily substance.

1H-NMR [DCl3/TMS δ (ppm)]: is 4.21 (2H, s), of 3.95 (3H, s), was 2.76 (2H, s), of 2.38 (3H, s), of 2.34 (3H, s)to 2.13 (3H, s), 1,42 (6N, C).

<Example 36>

Getting 5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyaminomethyl)thiophene-3-elmersolver]-2-isoxazoline (compound of the present invention No. 2-0001)

To a solution of 0.4 g (1.2 mmol) of 5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyaminomethyl)thiophene-3-immedilty]-2-isoxazoline in 30 ml of chloroform, add 0,61 g m-holdem what unadventurous acid (purity 70%, 3.5 mmol) under cooling with ice. The mixture is stirred for 1 hour and then at room temperature for 12 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The resulting residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane - ethyl acetate), to obtain 0.35 g (yield: 80%) of 5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyaminomethyl)thiophene-3-elmersolver]-2-isoxazoline in the form of white crystals (melting point 95,0-96,0°).

1H-NMR [DCl3/TMS δ (ppm)]: rate 4.79 (2H, s), of 3.95 (3H, s), with 2.93 (2H, s), 2,42 (3H, s), is 2.37 (3H, s), 2,17 (3H, s), 1,47 (6N, C).

<Example 37>

Getting 5,5-dimethyl-3-(4-triptorelin-3-immedilty)-2-isoxazoline (compound of the present invention No. 7-0003)

To a solution of 0.3 g (1.6 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 20 ml of N,N-dimethylformamide added 0.26 g of sodium hydrosulfide (purity 70%, 4.6 mmol). The mixture is stirred for 1 hour. To the mixture is added to 0.22 g (16 mmol) of anhydrous potassium carbonate and 0.25 g (1.6 mmol) of rongalite. The resulting mixture was stirred for 2 hours. To the mixture while cooling with ice, add 0.3 g (1.3 mmol) 3-methyl bromide-4-triptoreline. The resulting mixture was stirred at room temperature for 2 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane - ethyl acetate), to obtain 0.45 g (yield 98.9 per cent) of 5,5-dimethyl-3-(4-triptorelin-3-immedilty)-2-isoxazoline in the form of a yellow oily substance.

1H-NMR [DCl3/TMS δ (ppm)]: 8,98 (1H, s), to 8.70 (1H, d), 7,51 (1H, d), 4,47 (2H, s), and 2.79 (2H, s), 1,43 (6N, C).

<Example 38>

Getting 5,5-dimethyl-3-(4-triptorelin-3-elmersolver)-2-isoxazoline (compound of the present invention No. 7-0001) and 5,5-dimethyl-3-(4-triptorelin-N-oxide-3-elmersolver)-2-isoxazoline (compound of the present invention No. 7-0002)

To a solution of 0.45 g (1.6 mmol) of 5,5-dimethyl-3-(4-triptorelin-3-immedilty)-2-isoxazoline in 20 ml of chloroform, add 0,77 g m-chlormadinone KIS is the notes (purity 70%, 4.5 mmol) under cooling with ice. The mixture is stirred for 1 hour and then at room temperature for 12 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The resulting residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), to obtain 0.06 g (yield of 12.0%) of 5,5-dimethyl-3-(4-triptorelin-3-elmersolver)-2-isoxazoline in the form of light yellow crystals (melting point 77,0-80,0° (C) and 0.12 g (yield of 23.1%) of 5,5-dimethyl-3-(4-triptorelin-N-oxide-3-elmersolver)-2-isoxazoline in the form of white crystals (temperature melting 114,0-116,0°).

For 5,5-Dimethyl-3-(4-triptorelin-3-elmersolver)-2-isoxazoline

1H-NMR [DCl3/TMS δ (ppm)]: 8,98 (1H, s), 8,84 (1H, d), to 7.64 (1H, d), to 4.92 (2H, s)to 3.09 (2H, s), 1,52 (6N, C).

For 5,5-Dimethyl-3-(4-triptorelin-N-oxide-3-elmersolver)-2-isoxazoline

1H-NMR [DCl3/TMS δ (ppm): 8,50 (1H, C)of 8.25 (1H, d), to 7.59 (1H, d), to 4.81 (2H, s), of 3.12 (2H, s), 1,53 (6N, C).

<Example 39>

Getting 5,5-dimethyl-[(4-methoxy-6-cryptomaterial-5-yl)methylthio]-2-isoxazoline (compound of the present invention No. 8-0002)

To a solution of 0.35 g (2.00 mmol) of 5,5-dimethyl-3-methylsulphonyl-2-isoxazoline in 10 ml of N,N-dimethylformamide added at room temperature, 0.32 g of sodium hydrosulfide (purity 70%, 4.00 mmol). The mixture is stirred for 2 hours. To the reaction mixture are added 0.28 g (2.00 mmol) of anhydrous potassium carbonate, 0.31 g (2.00 mmol) of rongalit and 0.45 g (2.00 mmol) of 5-chloromethyl-4-methoxy-6-cryptomaterial. The resulting mixture was stirred at room temperature for 2 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel, to obtain 0.55 g (yield 85,9%) of 5,5-dimethyl-[(4-methoxy-6-cryptomaterial-5-yl)methylthio]-2-isoxazoline.

1H-NMR [DCl3/TMS δ (ppm)]: 8,81 (1H, s), of 4.44 (2H, d), of 4.12 (3H, s), of 2.81 (2H, s), 1,45 (6N, C).

<Example 40>

Getting 5,5-dimethyl-[(4-methoxy-6-cryptomaterial-yl)methylsulphonyl]-2-isoxazoline (compound of the present invention No. 8-0001)

To a solution of 0.55 g (1,71 mmol) of 5,5-dimethyl-[(4-methoxy-6-cryptomaterial-5-yl)methylthio]-2-isoxazoline in 20 ml of chloroform added to 1.05 g m-chlormadinone acid (purity 70%, to 4.28 mmol) under cooling with ice. The mixture is stirred for 1 hour and then at room temperature for 4 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The resulting residue is purified column chromatography on silica gel, to obtain 0.45 g (yield of 75.0%) 5,5-dimethyl-[(4-methoxy-6-cryptomaterial-5-yl)methylsulphonyl]-2-isoxazoline white like feathers crystals (melting point 175-176°).

1H-NMR [DCl3/TMS δ (ppm)]: 8,89 (1H, s)5,00 (2H, d), to 4.41 (3H, s), 3,11 (2H, s), 1,53 (6N, C).

<Example 41>

Obtaining 3-(5,5-dimethyl-2-isoxazolin-3-altimeter)-2-trifluoromethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (compound of the present invention No. 3-0033)

A solution of 0.82 g (2.3 mmol) of 3-[5-chloro-1-(3-hydroxypropyl)-3-trifluoromethyl-1H-pyrazole-4-ILM is tilty]-5,5-dimethyl-2-isoxazol in 5 ml of N,N-dimethylformamide is added dropwise to a suspension of 0.11 g (2.8 mmol) of sodium hydride in 15 ml of N,N-dimethylformamide. At the end of the addition the mixture is stirred for 30 min at room temperature, then heated to 100°C and stirred for 1 hour for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous citric acid solution and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation, gain of 0.77 g (yield 100%) of 3-(5,5-dimethyl-2-isoxazolin-3-altimeter)-2-trifluoromethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine.

1H-NMR [DCl3/TMS δ (ppm)]: 4,37 (2H, t), 4,19 (2H, t), is 4.15 (2H, s), 2,80 (2H, s), 2,31 (2H, m), 1,42 (6N, C).

<Example 42>

Obtaining 3-(5,5-dimethyl-2-isoxazolin-3-ylsulphonyl)-2-trifluoromethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (compound of the present invention No. 3-0019)

To a solution of 0.77 g (2.3 mmol) of 3-(6,7-dihydro-3-trifluoromethyl-5H-pyrazolo[5,1-b][1,3]oxazin-4-immedilty)-5,5-dimethyl-2-isoxazoline in 20 ml of chloroform added to 1.25 g of m-chlormadinone acid (purity 70%, 5.1 mmol) under cooling with ice. The mixture is stirred for 1 hour and then at room temperature for 12 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic is Loy washed with hydrogen sulfite solution of sodium aqueous sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The resulting residue is purified column chromatography on silica gel, to obtain 0.36 g (yield 43%) of 3-(5,5-dimethyl-2-isoxazolin-3-ylsulphonyl)-2-trifluoromethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine in the form of a white powder (melting point 151,0-to 152.0°).

1H-NMR [DCl3/TMS δ (ppm)]: 4,47 (2H, s), and 4.40 (2H, t)to 4.23 (2H, t)to 3.09 (2H, s), of 2.34 (2H, m), 1,50 (6N, C).

The numbers of compounds are presented in tables 11-20, correspond to the numbers of the examples.

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Examples obtain the intermediate compounds

<Reference example 1>

Obtain 3-chloro-5,5-dimethyl-2-isoxazoline

To a solution of 182,7 g (2.05 mol) aldoxime Glyoxylic acid in 2 l of 1,2-dimethoxyethane gradually added at a temperature of 65-70°534,0 g (4.0 mol) of N-chlorosuccinimide. The mixture is refluxed for 1 hour. Then to the mixture under cooling with ice add 1440,0 g (14.4 mol) of potassium bicarbonate and 10 ml of water. Then add 360,0 g (6.4 mol) of 2-methylpropene. The resulting mixture was stirred at room temperature for 24 hours for reaction. The reaction mixture was poured into water, then extracted with diisopropyl ether. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, get to 107.7 g (yield of 40.0%) 3-chloro-5,5-dimethyl-2-isoxazoline in the form of a yellow viscous liquid.

1H-NMR [CDCl3/TMS δ (ppm)]: at 2.93 (2H, s), 1,47 (6N, C).

<Reference example 2>

Obtain 3-chloro-5-ethyl-5-methyl-2-isoxazoline

To rest the ru 20.6 g (231,7 mmol) aldoxime Glyoxylic acid in 500 ml of 1,2-dimethoxyethane gradually added at a temperature of 60° With 61,9 g (463,4 mmol) N-chlorosuccinimide. After the addition the mixture is refluxed for 10 minutes Then to the mixture while cooling with ice, add 50 ml (463,4 mmol) of 2-methyl-1-butene, 98.9 g (1,622 mmol) of potassium bicarbonate and 10 ml of water. The resulting mixture was stirred for 12 hours for reaction. The reaction mixture was poured into water, then extracted with n-hexane. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent gain of 13.9 g (yield 40,6%) 3-chloro-5-ethyl-5-methyl-2-isoxazoline in the form of a yellow viscous liquid.

1H-NMR [CDCl3/TMS δ (ppm)]: only 2.91 (2H, Avkw, J=17,0Δν=46,1 Hz)of 1.73 (2H, q), of 1.42 (3H, s)to 0.96 (3H, t).

<Reference example 3>

Obtaining 3-benzylthio-5,5-dimethyl-2-isoxazoline

To a solution of 2.8 g (to 22.5 mmol) benzylmercaptan in 50 ml of N,N-dimethylformamide in a nitrogen atmosphere add 3.2 g (23.2 mmol) of anhydrous potassium carbonate and 3.0 g (to 22.5 mmol) 3-chloro-5,5-dimethyl-2-isoxazoline. The mixture was stirred at 100°C for 2 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride in the decree is " a big order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel, to obtain 3.1 g (yield 62,0%) 3 benzylthio-5,5-dimethyl-2-isoxazoline in the form of a yellow oily substance (nD20= 1,5521).

1H-NMR [CDCl3/TMS δ (ppm)]: 7,24-7,39 (5H, m), 4.26 deaths (2H, s), 2,77 (2H, s), 1,40 (6N, C).

<Reference example 4>

Obtaining 3-(2,6-diferencialine)-5-ethyl-5-methyl-2-isoxazoline

To a solution of 4.1 g (15.0 mmol) of 3-(2,6-diferentially)-5-ethyl-5-methyl-2-isoxazoline in 50 ml of chloroform added 4.6 g m-chlormadinone acid (purity 70%, of 18.8 mmol) under cooling with ice. The mixture is stirred for 1 hour and then at room temperature for 12 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The resulting residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), to obtain 1.5 g (o is d: 34,8%) of 3-(2,6-diferencialine)-5-ethyl-5-methyl-2-isoxazoline in the form of a white powder (melting point 30° With or below).

1H-NMR [CDCl3/TMS δ (ppm)]: 7,39-7,28 (1H, m), 7.03 is-6,94 (2H, m), to 4.38 (2H, s), 3.04 from (1H, Avkw, J=17,2Δν=85,7 Hz), 3,12 (1H, s)of 1.75 (2H, m)of 1.44 (3H, s)of 1.41 (3H, s)to 0.97 (3H, m).

<Reference example 5>

Obtaining 3-(2,6-differentiality)-5-ethyl-5-methyl-2-isoxazoline

To a solution of 0.8 g (2.8 mmol) of 3-(2,6-diferencialine)-5-ethyl-5-methyl-2-isoxazoline in 50 ml of chloroform, add 1.0 g m-chlormadinone acid (purity 70%, 4.1 mmol) under cooling with ice. The mixture is stirred for 1 hour and then at room temperature for 12 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer was washed with hydrogen sulfite solution sodium, aqueous sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The resulting residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), to obtain 0.6 g (yield of 75.0%) 3-(2,6-differentiality)-5-ethyl-5-methyl-2-isoxazoline in the form of a white powder (melting point 64-65°).

1H-NMR [CDCl3/TMS δ (ppm)]: of 7.36-7,46 (1H, m), 6,98? 7.04 baby mortality (2H, m), to 4.73 (2H, s) totaling 3.04 (1H, Avkv, J=17,2Δν=51,1 Hz), 1.77 in (2N, q), of 1.46 (3H, s)to 0.97 (3H, t).

<Reference example 6>

Getting 5,5-dimethyl-3-methylsulphonyl-2-isoxazoline

To a solution of 143,0 g (1.07 mol) of 3-chloro-5,5-dimethyl-2-isoxazoline in 500 ml of N,N-dimethylformamide is added dropwise under ice cooling for 1 kg of an aqueous solution of methanolate sodium content of 15%, 2.14 mmol). The mixture is stirred at room temperature for 12 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, get 115,0 g (yield 74,1%) of 5,5-dimethyl-3-methylthio-2-isoxazoline. This residue (741,2 mmol) dissolved in 1 l of chloroform. To the solution while cooling with ice add 392,0 g m-chlormadinone acid (purity 70%, of 1.59 mol). The resulting mixture was stirred for 1 hour and then at room temperature for 12 hours for reaction. Upon completion of the reaction, the remainder of the m-chlormadinone acid is filtered off. The obtained filtrate was washed with hydrogen sulfite solution of sodium with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution in this order and then dried over anhydrous Sul is blockhead magnesium. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue was washed with diisopropyl ether, receive and 77.6 g (yield 59,1%) of 5,5-dimethyl-3-methylsulphonyl-2-isoxazoline in the form of a white powder (melting point of 82-84°).

1H-NMR [CDCl3/TMS δ (ppm)]: 3,26 (3H, s), of 3.12 (2H, s)and 1.51 (6N, C).

<Reference example 7>

Getting 5,5-dimethyl-3-ethylthio-2-isoxazoline

To a solution containing 3-chloro-5,5-dimethyl-2-isoxazolin add 1500 ml of an aqueous solution containing 560 g (9.0 mol) of ethyl mercaptan and 360,0 g (9.0 mol) of sodium hydroxide. The mixture was stirred at 60-70°C for 16 h for the reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, get, 270.0 g of crude 5,5-dimethyl-3-ethylthio-2-isoxazoline in the form of a dark red oily substance.

<Reference example 8>

Getting 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline

In 1 liter of chloroform is dissolved, 270.0 g (1.7 mol) of crude oily 5,5-dimethyl-3-ethylthio-2-oxazoline. To the solution while cooling with ice add auth 1050 g m-chlormadinone acid (purity 70%, 6.1 mol). The resulting mixture was stirred for 1 hour and then at room temperature for 12 hours for reaction. After confirming completion of the reaction residue m-chlormadinone acid is filtered off. The obtained filtrate was washed with hydrogen sulfite solution sodium, aqueous sodium hydrogen carbonate solution, water and aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue was washed with n-hexane, get 133,6 g (yield of 65.4%) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in the form of a white powder.

<Reference example 9>

Obtain 1-phenyl-3-trifluoromethyl-1H-pyrazole-5-ol

To a solution of 34.1 g (184,9 mmol) ethyltrichlorosilane in 500 ml of ethanol are added 20 g (184,9 mmol) of phenylhydrazine and 4 ml of concentrated hydrochloric acid. The mixture is refluxed for 1 hour for reaction. Upon completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove most of the contained solvent. The residue is mixed with water to precipitate crystals. The crystals are filtered, washed with water up until the filtrate becomes neutral, and dried, get to 37.1 g (yield 87,9%) of 1-phenyl-3-trifluoromethyl-1H-pyrazole-5-ol as a brown is so-and-yellow crystals.

1H-NMR [CDCl3/TMS δ (ppm)]: 7,68-7,41 (5H, m), 5,86 (1H, s), 3,71 (1H, s).

<Reference example 10>

Getting 5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde

To 7.7 g (of 105.2 mmol) of N,N-dimethylformamide while cooling with ice add to 33.6 g (219,1 mmol) of phosphorus oxychloride. To the mixture at room temperature, add 20 g (87,7 mmol) 1-phenyl-3-trifluoromethyl-1H-pyrazole-5-ol. The resulting mixture was refluxed for 1 hour for reaction. Upon completion of the reaction, the reaction mixture was poured into water with ice cooling, and then extracted with chloroform. The obtained organic layer was washed with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), gain of 19.1 g (yield 79,1%) 5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde in the form of white crystals.

1H-NMR [CDCl3/TMS δ (ppm)]: 10,06 (1H, s), EUR 7.57 (5H, s).

<Reference example 11>

Receive (5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-yl)methanol

A solution of 0.21 g (5.5 mmol) of sociallyengaged in 70 ml of THF is cooled to -30aboutthe. To the solution is gradually added a solution of 3 g (10.9 mmol) of 5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde in 30 ml of tetrahydrofuran. The resulting mixture was stirred at -30°C for 30 min for the reaction. Upon completion of the reaction, add ethyl acetate and then stirred. Then add water, then stirred for some time. The reaction mixture was filtered in a vacuum. The filtrate is extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 3.0 g (yield of 99.9%) (5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-yl)methanol as white crystals.

1H-NMR [CDCl3/TMS δ (ppm)]: 7,54-7,51 (5H, m), 4,71 (2H, d), to 1.79 (1H, ush.).

<Reference example 12>

Getting 4-methyl bromide-5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole

A solution of 3.0 g (10.9 mmol) of (5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-yl)methanol in 60 ml of diethyl ether cooled to -10aboutC. To the solution was added 1.0 g (3.8 mmol) of tribromide phosphorus. The mixture is stirred at room temperature for 1 hour for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and the one solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 3.6 g (yield 95,8%) 4-methyl bromide-5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole as white crystals.

1H-NMR [CDCl3/TMS δ (ppm)]: 7,58-of 7.48 (5H, m), 4,48 (2H, s).

<Reference example 13>

Getting 5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde

To a solution of 33.0 g (120,1 mmol) 5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde in 500 ml of dimethyl sulfoxide added to 10.5 g (180,2 mmol) of potassium fluoride. The mixture was stirred at 100°C for 2 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), gain of 26.5 g (yield 85.0 per cent) 5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde.

1H-NMR [CDCl3/TMS δ (ppm)]: 9,96 (1H, s), 7.68 per-7,51 (5H, m).

<Reference example 14>

Receive (5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-yl)methanol

To a solution of 1.6 g (41,0 mmol) Brogi the reed of sodium in 300 ml of methanol while cooling with ice add a solution of 26.5 g (102,5 mmol) 5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde in 200 ml of methanol. The resulting mixture was stirred at 0°C for 30 min for the reaction. After the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 28.5 g (yield 100%) of (5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-yl)methanol.

1H-NMR [CDCl3/TMS δ (ppm)]: the 7.65 7,41 (5H, m), and 4.68 (2H, d), is 1.73 (1H, t).

<Reference example 15>

Getting 4-methyl bromide-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole

A solution of 27.5 g (105,7 mmol) (5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-yl)methanol in 300 ml of diethyl ether cooled to 0°C. To the solution was added 10.0 g (37,0 mmol) tribromide phosphorus. The mixture is stirred at room temperature for 2 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with diethyl ether. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent gain of 30.3 g (yield 88,8%) 4-methyl bromide-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole.

1H-NMR [CDCl3/TMS δ (ppm)] 7,66-7,42 (5H, m), of 4.44 (2H, s).

<Reference example 16>

Obtain 1-tert-butyl-3-trifluoromethyl-1H-pyrazole-5-ol

To a solution of 552,3 g (3.0 mol) of ethyltrichlorosilane in 1500 ml of ethanol add 373,8 g (3.0 mol) of the hydrochloride tert-butylhydrazine and 50 ml of concentrated hydrochloric acid. The mixture is refluxed for 2 days for a reaction. Upon completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove most of the contained solvent. The residue was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue was washed with n-hexane, get 369,0 g (yield 59,1%) of 1-tert-butyl-3-trifluoromethyl-1H-pyrazole-5-ol as a white powder.

<Reference example 17>

Obtain 1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde

To 87,7 g (1.2 mol) of N,N-dimethylformamide while cooling with ice add 462,0 g (3.0 mol) of phosphorus oxychloride. To the mixture at room temperature add 208,2 g (1.0 mol) of 1-tert-butyl-3-trifluoromethyl-1H-pyrazole-5-ol. The resulting mixture was refluxed 10 hours for reaction. At the end react and the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer is washed with water, 5%aqueous sodium hydroxide solution and water in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), 131, 5mm receive g (yield of 21.7%) of 1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde in the form of white crystals.

1H-NMR [CDCl3/TMS δ (ppm)]: becomes 9.97 (1H, d), 1,76 (N, C).

<Reference example 18>

Obtain (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-yl)methanol

A solution of 39.9 g (156,9 mmol) 1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde in 300 ml of methanol is cooled to 0°C. To the solution is gradually added 6.5 g (172,6 mmol) of sodium borohydride. The resulting mixture was stirred at room temperature for 3 hours for reaction. After the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent gain of 37.7 g (yield 93,6%) (1-tert-butyl-5-chloro-3-Tr is formetal-1H-pyrazole-4-yl)methanol.

1H-NMR [CDCl3/TMS δ (ppm)]: 4,60 (2H, d), 1,72 (N, C), 1,58 (1H, t).

<Reference example 19>

Getting 4-methyl bromide-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole

A solution of 9.2 g (35,7 mmol) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-yl)methanol in 100 ml of diethyl ether cooled to -10°C. To the solution was added 11.6 g (42,9 mmol) tribromide phosphorus. The mixture is stirred at room temperature overnight for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with diethyl ether. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 10.0 g (87.3%) 4-methyl bromide-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole.

<Reference example 20>

Obtain (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-yl)methanethiol

Add to 43.5 g (136,1 mmol) 4-methyl bromide-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole to a solution of 21.8 g of the hydrate of sodium hydrosulfide (purity 70%, 272,2 mmol) in 300 ml of N,N-dimethylformamide. The mixture is stirred at room temperature overnight for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with diethyl ether. Received the first organic layer is washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, receive and 32.3 g (yield of 87.0%) (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole-4-yl)methanethiol.

1H-NMR [CDCl3/TMS δ (ppm)]: the 3.65 (2H, d), 1,90 (1H, t), 1,70 (N, C).

<Reference example 21>

Obtain (1-tert-butyl-5-methoxy-3-trifluoromethyl-1H-pyrazole

To a solution of 18.8 g (90,3 mmol) 1-tert-butyl-3-trifluoromethyl-1H-pyrazole-5-ol in 100 ml of N,N-dimethylformamide added at room temperature 15.0 g (108,4 mmol) of anhydrous potassium carbonate and 19.3 g (135,5 mmol) under the conditions. The mixture is stirred for 15 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with diethyl ether. The obtained organic layer was washed with water

and an aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, get 20,0 g (yield 99,8%) of 1-tert-butyl-5-methoxy-3-trifluoromethyl-1H-pyrazole.

<Reference example 22>

Obtain 1-tert-butyl-4-chloromethyl-5-methoxy-3-trifluoromethyl-1H-pyrazole

To a solution of 20.0 g (90,1 mmol) 1-tert-butyl-5-methoxy-3-trifluoromethyl-1H-pyrazole in 90 ml of acetic acid added to 5.4 g Performa (180,2 mmol based on formaldehyde) and 20 ml of concentrated chlorophyll is estevadeordal acid. The mixture was stirred at 60°C for 30 min for the reaction. After the reaction mixture was poured into water, then extracted with diisopropyl ether. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent gain of 21.7 g (yield 89,0%) of 1-tert-butyl-4-chloromethyl-5-methoxy-3-trifluoromethyl-1H-pyrazole.

<Reference example 23>

Obtain 3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole

To a solution of 10.0 g (a 60.2 mmol) of 3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazole in 50 ml of N,N-dimethylformamide added at room temperature 10.0 g (72,3 mmol) of anhydrous potassium carbonate and 12.8 g (90,3 mmol) under the conditions. The mixture is stirred for 15 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with diethyl ether. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent gain of 9.8 g (yield 90.7 percent) of 3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole.

<Reference example 24>

Getting 4-chloromethyl-3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole

To a solution of 1.00 g (5.6 m is ol) 3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole in 25 ml acetic acid is added 0.45 g of paraform (15.0 mmol based on formaldehyde) and 5 ml of concentrated hydrochloric acid. The mixture was stirred at 80°C for 2 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water and neutralized with potassium carbonate, and then extracted with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), get 0,83 g (65.0%) of 4-chloromethyl-3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole.

<Reference example 25>

Getting 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde

To a solution 60,4 g (282,7 mmol) 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde in 700 ml of dimethyl sulfoxide add 42,0 g (711,9 mmol) of potassium fluoride. The mixture is stirred at a temperature of from 120 to 140°C for 5 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography n the silica gel (the solvent: hexane-ethyl acetate), get to 36.8 g (yield 66,0%) 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde.

<Reference example 26>

Receive (5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-yl)methanol

To a solution of 3.9 g (102,6 mmol) of sodium borohydride in 500 ml of methanol while cooling with ice add solution to 36.8 g (187,6 mmol) 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde in 200 ml of methanol. The resulting mixture was stirred at 0°C for 30 min for the reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, get of 35.4 g (yield of 95.4%) (5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-yl)methanol.

<Reference example 27>

Getting 4-methyl bromide-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole

A solution of 35.4 g (178,7 mmol) 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-methanol in 500 ml of diethyl ether cooled to -30°C. To the solution was added of 54.0 g (199,5 mmol) tribromide phosphorus. The mixture is stirred at room temperature for 12 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted dieti the new ether. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent gain of 31.4 g (yield 80,8%) 4-methyl bromide-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole.

<Reference example 28>

Receiving (etoxycarbonyl)malondialdehyde

Washed several times of 12.6 g of sodium hydride (purity 60%, 525,0 mmol) by decantation with diethyl ether and then prepare a solution in 500 ml of diethyl ether. To the solution in a stream of nitrogen at a temperature of from 0 to 10°add 194 g (2.6 mmol) of ethylformate and 50 g (262,0 mmol) ethyl-3,3-diethoxypropionate. The resulting mixture was stirred at room temperature for 15 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, and then washed with diethyl ether. The resulting aqueous layer was adjusted to pH 1 with hydrochloric acid and then extracted with dichloromethane. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, get to 37.6 g (yield 100%) of crude (etoxycarbonyl)of malondialdehyde in the form of a dark red oily substance is.

1H-NMR [CDCl3/TMS δ (ppm)]: a 9.09 (2H, s), of 5.26 (1H, s), 4,27 (2H, q), of 1.28 (3H, t).

<Reference example 29>

Getting ethyl-1H-pyrazole-4-carboxylate

To a solution of 27.6 g (192 mmol) (etoxycarbonyl) of malondialdehyde in 150 ml of ethanol under cooling with ice added 6.2 g (193 mmol) of hydrazine. The mixture is stirred at room temperature for 17 hours for reaction. The reaction mixture was subjected to vacuum distillation to remove the contained ethanol. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of dichloromethane-ethyl acetate), gain of 19.4 g (yield 72,4%) ethyl-1H-pyrazole-4-carboxylate as yellow crystals.

1H-NMR [CDCl3/TMS δ (ppm)]: 8,08 (2H, s), and 5.30 (1H, s), or 4.31 (2H, q), of 1.36 (3H, t).

<Reference example 30>

Getting ethyl-1-ethyl-1H-pyrazole-4-carboxylate

To a solution of 1.5 g (about 10.7 mmol) ethyl-1H-pyrazole-4-carboxylate in 50 ml of N,N-dimethylformamide added 3.7 g (26.8 mmol) of anhydrous potassium carbonate and 4.2 g (to 26.6 mmol) ethyliodide. The mixture is stirred at room temperature for 20 hours for reaction. After the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum is distilled to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), to obtain 1.6 g (yield 88,9%) ethyl-1-ethyl-1H-pyrazole-4-carboxylate as a yellow oily substance.

1H-NMR [CDCl3/TMS δ (ppm)]: of 7.90 (2H, s), 4,28(2H, HF), 4,18 (2H, HF)and 1.51 (3H, t), of 1.35 (3H, t).

<Reference example 31>

Getting ethyl-3,5-dichloro-1-ethyl-1H-pyrazole-4-carboxylate

In a sealed glass tube placed 1.6 g (9.5 mmol) ethyl-1-ethyl-1H-pyrazole-4-carboxylate and 5.1 g (to 38.3 mmol) N-chlorosuccinimide. The mixture is allowed the opportunity to react at 160°C for 6 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with carbon tetrachloride and chloroform and filtered under vacuum. The obtained filtrate (organic layer) was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), to obtain 1.0 g (yield of 44.2%) ethyl-3,5-dichloro-1-ethyl-1H-pyrazole-4-carboxylate as a yellow oily substance.

1H-NMR [CDCl3/TMS δ (ppm)]: 4,36 (2H, q), is 4.21 (2H, q), of 1.44 (3H, t)to 1.38 (3H, t).

lt; Reference example 32>

Obtain (3,5-dichloro-1-ethyl-1H-pyrazole-4-yl)methanol

A solution of 0.16 g (4.2 mmol) of sociallyengaged in 70 ml of THF is cooled to -50°C. To the mixture slowly add a solution of 1.0 g (4.2 mmol) of ethyl-3,5-dichloro-1-ethyl-1H-pyrazole-4-carboxylate in 30 ml of tetrahydrofuran. The resulting mixture was stirred at -50°C for 3 hours for reaction. After confirming the completion of reaction, add ethyl acetate and then stirred for some time. Add water and then stirred for some time. The resulting mixture was filtered under vacuum. The filtrate is extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent gain of 0.82 g (yield 100%) of (3,5-dichloro-1-ethyl-1H-pyrazole-4-yl)methanol as a brown oily substance.

1H-NMR [CDCl3/TMS δ (ppm)]: to 4.52 (2H, s)to 4.16 (2H, q), USD 1.43 (3H, t).

<Reference example 33>

Getting 4-methyl bromide-3,5-dichloro-1-ethyl-1H-pyrazole

A solution of 0.82 g (4.2 mmol) of (3,5-dichloro-1-ethyl-1H-pyrazole-4-yl)methanol in 50 ml of diethyl ether cooled to -30°C. To the solution was added 1.3 g (4.8 mmol) of tribromide phosphorus. The mixture is stirred at room temperature for 12 h for proteini the reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 0.9 g (yield 81,8%) 4-methyl bromide-3,5-dichloro-1-ethyl-1H-pyrazole as a yellow oily substance.

1H-NMR [CDCl3/TMS δ (ppm)]: to 4.33 (2H, s), of 4.13 (2H, q), USD 1.43 (3H, t).

<Reference example 34>

Obtaining 3-deformity-1-methyl-1H-pyrazole-5-ol

To a solution of 30.0 g (180,6 mmol) ethyldiethanolamine in 200 ml ethanol add to 8.3 g (180,6 mmol) methylhydrazine and 5 ml of concentrated hydrochloric acid. The mixture is refluxed for 2 days for a reaction. Upon completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove most of the contained solvent. The residue poured into water. Bring the pH of the mixture to 4 using citric acid and extracted with ethyl acetate. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. the STATCOM purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), get a 8.9 g (yield 33.3%) of 3-deformity-1-methyl-1H-pyrazole-5-ol.

<Reference example 35>

Getting 5-chloro-3-deformity-1-methyl-1H-pyrazole-4-carbaldehyde

7.9 g (108,0 mmol) of N,N-dimethylformamide while cooling with ice add to 41.6 g (270,1 mmol) of phosphorus oxychloride. To the mixture at room temperature add 8.0 g (54,0 mmol) 3-deformity-1-methyl-1H-pyrazole-5-ol. The resulting mixture was refluxed 4 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water with ice cooling, and then extracted with chloroform. The obtained organic layer is washed with water, 5%aqueous sodium hydroxide solution and water in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), gain of 7.7 g (yield 73,3%) 5-chloro-3-deformity-1-methyl-1H-pyrazole-4-carbaldehyde in the form of white crystals.

1H-NMR [CDCl3/TMS δ (ppm)]: 9,96 (1H, s), make 6.90 (1H, t, J=53,3 Hz), 3,93 (3H, s).

<Reference example 36>

Receive (5-chloro-3-deformity-1-methyl-1H-pyrazole-4-yl)methanol

A solution of 7.2 g (37,0 mmol) 5-chloro-3-deformity-1-methyl-1H-pyrazole-4-carbaldehyde in 100 ml of methanol, ohla is to give 0° C. To the solution is gradually added 2.1 g (of 55.5 mmol) of sodium borohydride. The resulting mixture was stirred at room temperature for 3 hours for reaction. After the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 3.8 g (yield of 52.1%) (5-chloro-3-deformity-1-methyl-1H-pyrazole-4-yl)methanol.

1H-NMR [CDCl3/TMS δ (ppm)]: 6,70 (1H, t, J=40,8 Hz), 4,63 (2H, s), 3,86 (3H, s)to 1.79 (1H, ush.).

<Reference example 37>

Getting 4-methyl bromide-5-chloro-3-deformity-1-methyl-1H-pyrazole

A solution of 2.0 g (10.0 mmol) of (5-chloro-3-deformity-1-methyl-1H-pyrazole-4-yl)methanol in 50 ml of diethyl ether cooled to -10°C. To the solution was added 1.0 g (3.5 mmol) of tribromide phosphorus. The mixture is stirred at room temperature overnight for reaction. Upon completion of the reaction, the reaction mixture was poured into water with ice cooling, and then extracted with diethyl ether. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained rest is ritala, obtain 2.6 g (yield 100%) 4-methyl bromide-5-chloro-3-deformity-1-methyl-1H-pyrazole.

<Reference example 38>

Getting epirate of oxime triptoreline

To a solution of 50.0 g (347,0 mmol) polyetherurethane triperoxonane aldehyde in 80 ml of methanol add 24,1 g (347,0 mmol) of hydroxylamine hydrochloride and 160 ml of water. To the mixture dropwise while cooling with ice add 80,0 g 50%aqueous sodium hydroxide solution (1.7 mol). After adding the resulting mixture was stirred at room temperature for 6 hours for reaction. Upon completion of the reaction, add 10%hydrochloric acid to establish a pH of 6. The resulting mixture was extracted with diethyl ether. The extract is subjected to vacuum distillation to remove the contained solvent. The residue is subjected to distillation, get to 24.7 g (yield 38,0%) epirate of oxime triptoreline.

<Reference example 39>

Getting epirate of cryptorchidectomy

The solution to 38.8 g (218,0 mmol) of N-bromosuccinimide in 125 ml of N,N-dimethylformamide under ice cooling are added to a solution of 24.7 g (131,7 mmol) epirate of oxime triptoreline in 50 ml of N,N-dimethylformamide. The mixture is stirred at room temperature for 3 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with diethyl ether. Receiving the hydrated organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is distilled receive a 33.3 g (yield 95,0%) epirate of cryptorchidectomy as a brown oily substance.

1H-NMR [CDCl3/TMS δ (ppm)]: of 9.30 (1H, s).

<Reference example 40>

Getting 4-etoxycarbonyl-5-methyl-3-cryptomaterial

To a solution of 6.7 g (51,3 mmol) ethylacetoacetate in 80 ml of methanol is added 2.8 g (51,3 mmol) of sodium methoxide. To the mixture while cooling with ice add a solution of 5.0 g (18,8 mmol) epirate of cryptorchidectomy in 20 ml of methanol. The resulting mixture was stirred at room temperature for 3 hours for reaction. Upon completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the contained solvent. To the residue water is added, then extracted with chloroform. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane-ethyl acetate), to obtain 2.9 g (yield 69,0%) 4-etoxycarbonyl-5-methyl-3-cryptomaterial in the form of colorless maslanik the CSOs substances.

1H-NMR [CDCl3/TMS δ (ppm)]: 4,36 (2H, HF), 2,77 (3H, s)to 1.37 (3H, t).

<Reference example 41>

Receive (5-methyl-3-cryptometrics-4-yl)methanol

A solution of 0.16 g (4.2 mmol) of sociallyengaged in 15 ml of THF is cooled to 0°C. To the solution slowly add a solution of 0.93 g (4.2 mmol) of 4-etoxycarbonyl-5-methyl-3-cryptomaterial in 15 ml of THF. The mixture was stirred at 0°C for 1 hour for reaction. Upon completion of the reaction, add ethyl acetate and then stirred for some time. Add water and mix for some time. The resulting mixture was filtered under vacuum. The filtrate is extracted with diethyl ether. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 0.5 g (yield 60,0%) (5-methyl-3-cryptometrics-4-yl)methanol.

1H-NMR [CDCl3/TMS δ (ppm)]: 4,60 (2H, d), of 2.54 (3H, s)of 1.66 (1H, ush.).

<Reference example 42>

Getting 4-methyl bromide-5-methyl-3-cryptomaterial

A solution of 0.45 g (2.5 mmol) (5-methyl-3-cryptometrics-4-yl)methanol in 10 ml of diethyl ether cooled to 0°C. To the solution was added 0.2 g (8.9 mmol) of tribromide phosphorus. The mixture is stirred at room temperature for 1 h for p is Oceania reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with diethyl ether. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 0.5 g (yield 74,0%) 4-methyl bromide-5-methyl-3-cryptomaterial.

1H-NMR [CDCl3/TMS δ (ppm)]: or 4.31 (2H, d), of 2.51 (3H, s).

<Reference example 43>

Receive (5-chloro-3-metalization-4-yl)methanol

A solution of 2.06 g (10.0 mmol) of ethyl-5-chloro-3-metalization-4-carboxylate in 10 ml of THF at -30°With added dropwise to a solution of 0.42 g (11.0 mmol) sociallyengaged in 10 ml of THF. The mixture is stirred at the same temperature for 1 hour for reaction. After confirming the completion of reaction, to the reaction mixture are added ethyl acetate. The resulting mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel, to obtain 1.50 g (yield of 91.5%) (5-chloro-3-metalization-4-yl)methanol.

<Reference example 44&g;

Getting 4-chloromethyl-5-chloro-3-methylisothiazolone

To a solution of 1.50 g (9,15 mmol) (5-chloro-3-metalization-4-yl)methanol in 10 ml of chloroform added at room temperature 3,26 g (27,44 mmol) of thionyl chloride. The mixture is stirred for 3 hours for reaction. After confirming completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the contained solvent, receive a rate of 1.67 g (yield quantitative) of 4-chloromethyl-5-chloro-3-methylisothiazolone.

<Reference example 45>

Obtaining methyl-4-triftoratsetofenona

To a solution of 4.6 g (24,1 mmol) 4-triftormetilfosfinov acid in 70 ml of N,N-dimethylformamide added 6.7 g (to 48.6 mmol) of anhydrous potassium carbonate and 6.9 g (to 48.6 mmol) under the conditions. The mixture is stirred at room temperature for 12 hours for reaction. After confirming completion of the reaction the mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane - ethyl acetate), get 2,77 g (yield 56,1%) of methyl-4-triftoratsetofenona in the form of a yellow oil is stogo substances.

1H-NMR [CDCl3/TMS δ (ppm)]: 9,11 (1H, s)of 8.92 (1H, d), to 7.64 (1H, d), to 3.99 (3H, s).

<Reference example 46>

Receive (4-triptorelin-3-yl)methanol

A solution of 0.37 g (9.7 mmol) of sociallyengaged in 100 ml of THF is cooled to -50°C. To the solution is gradually added dropwise a solution of 2.0 g (9.8 mmol) of 4-triftoratsetofenona in 30 ml of THF. The mixture was stirred at -50°C for 3 hours for reaction. After confirming the completion of reaction, add ethyl acetate and then stirred for some time. Add water and mix for some time. The reaction mixture is filtered under vacuum. The filtrate is extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane - ethyl acetate), to obtain 0.6 g (yield 35,3%) (4-triptorelin-3-yl)methanol as a yellow oily substance.

1H-NMR [CDCl3/TMS δ (ppm)]: 9,00 (1H, s), 8,73 (1H, d), 7,51 (1H, d), of 4.95 (2H, s).

<Reference example 47>

Obtaining 3-methyl bromide-4-triptoreline

A solution of 0.6 g (3.4 mmol) (4-triptorelin-3-yl)methanol at 0 ml of diethyl ether cooled to -30° C. To the solution was added 1.4 g (5.2 mmol) of tribromide phosphorus. The mixture is stirred at room temperature for 12 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, receive and 0.61 g (yield 75,3%) 3-methyl bromide-4-triptoreline in the form of a yellow oily substance.

1H-NMR [CDCl3/TMS δ (ppm)]: 8,88 (1H, s), 8,73 (1H, d), 7,54 (1H, d), 4.63 to (2N, C).

<Reference example 48>

Getting 5-bromo-4-hydroxy-6-cryptomaterial

To a solution of 49.2 g (300,0 mmol) 4-hydroxy-6-cryptomaterial in 600 ml of acetic acid at room temperature add 77,5 g (945,0 mmol) of anhydrous sodium acetate. To the mixture at 45°gradually add to 50.3 g (315 mmol) of bromine. The resulting mixture was stirred at the same temperature for 3 hours for reaction. After confirming completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the contained solvent. The residue was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and aqueous solution of chlorine is IDA sodium and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue was washed with n-hexane, get 38,9 g (yield 53,4%) 5-bromo-4-hydroxy-6-cryptomaterial.

<Reference example 49>

Getting 5-bromo-4-chloro-6-cryptomaterial

18.5 g (120,0 mmol) of phosphorus oxychloride are suspended 24,3 g (100.0 mmol) of 5-bromo-4-hydroxy-6-cryptomaterial. The mixture was stirred at 100°C for 2 hours for reaction. After confirming completion of the reaction, the reaction mixture was poured slowly into water, then extracted with chloroform. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel, get a 21.5 g (yield 82,4%) 5-bromo-4-chloro-6-cryptomaterial.

<Reference example 50>

Getting 5-bromo-4-methoxy-6-cryptomaterial

To a solution of 21.5 g (with 82.2 mmol) 5-bromo-4-chloro-6-cryptomaterial in 100 ml of methanol is added at room temperature of 16.7 ml of sodium methoxide (28%methanol solution, to 86.4 mmol). The mixture is stirred for reaction. After confirming completion of the reaction, the reaction mixtures is ü subjected to vacuum distillation to remove the contained solvent. The residue is poured into water, then extracted with chloroform. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue was washed with n-hexane, gain of 19.2 g (yield 91,0%) 5-bromo-4-methoxy-6-cryptomaterial.

<Reference example 51>

Getting 5-bromo-4-ethoxy-6-cryptomaterial

To a solution of 3.00 g (of $ 11.48 mmol) 5-bromo-4-chloro-6-cryptomaterial in 50 ml of ethanol is added at room temperature to 0.94 g (13,77 mmol) ethoxide sodium. The mixture is stirred for reaction. After confirming completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the contained solvent. The residue is poured into water, then extracted with chloroform. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel, gain of 2.44 g (yield of 82.9%) 5-bromo-4-ethoxy-6-cryptomaterial.

<Reference example 52>

Getting 4-methoxy-6-thrift methylpyrimidin-5-carbaldehyde

To a solution of 10.3 g (40.0 mmol) of 5-bromo-4-methoxy-6-cryptomaterial in 100 ml of tetrahydrofuran at temperatures from -65 to -60°gradually add 30,0 ml n-utility (1.6 mol/l solution in n-hexane, to 48.0 mmol). The mixture is stirred for 30 minutes To the mixture at the same temperature, add 3.6 g (48,0 mmol) ethylformate. The resulting mixture was stirred at the same temperature for 3 hours for reaction. The reaction mixture is poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel, to obtain 1.3 g (yield of 15.8%) 4-methoxy-6-cryptomaterial-5-carbaldehyde.

1H-NMR [CDCl3/TMS δ (ppm)]: 10,41 (1H, HF), 8,91 (1H, s), 4,18 (3H, s).

<Reference example 53>

Getting 4-ethoxy-6-cryptomaterial-5-carbaldehyde

The solution 5,76 g (21,3 mmol) 5-bromo-4-ethoxy-6-cryptomaterial in 250 ml of THF is cooled to -78°C. To the solution is gradually added dropwise to 22.6 ml of n-utility (1.6 mol/l solution in n-hexane, at 36.1 mmol). The mixture is stirred for 40 minutes To a mixture of 2.7 g (45,1 mmol) methylformate. The resulting mixture was stirred for 1.5 h for whom rotamania reaction. Upon completion of the reaction, add an aqueous solution of ammonium chloride. The mixture is extracted with diethyl ether. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane - ethyl acetate), get 3,82 g (yield of 81.6%) 4 ethoxy-6-cryptomaterial-5-carbaldehyde.

1H-NMR [CDCl3/TMS δ (ppm)]: 10,41 (1H, s), of 8.95 (1H, s), 4,63 (2H, HF), to 1.48 (3H, t).

<Reference example 54>

Receive (4-methoxy-6-cryptomaterial-5-yl)methanol

To a solution of 1.3 g (6.3 mmol) of 4-methoxy-6-cryptomaterial-5-carbaldehyde in 30 ml of methanol gradually at room temperature is added 0.24 g (6.3 mmol) of sodium borohydride. The mixture is stirred for 3 hours for reaction. After confirming completion of the reaction the mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, get 0,42 g (32.1%) (4-methoxy-6-trifloromethyl rimidine-5-yl)methanol.

1H-NMR [CDCl3/TMS δ (ppm)]: 8,93 (1H, s), to 4.81 (2H, s), 4,13 (3H, s), and 2.26 (1H, ush.).

<Reference example 55>

Receive (4 ethoxy-6-cryptomaterial-5-yl)methanol

The solution is 3.82 g (17,2 mmol) 4-ethoxy-6-cryptomaterial-5-carbaldehyde in 50 ml of methanol under ice cooling are added to a solution of 1.7 g (of 45.7 mmol) of sodium borohydride in 50 ml of methanol. The resulting mixture was stirred at 0°C for 1 hour for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, get of 3.77 g (yield of 97.8%) (4 ethoxy-6-cryptomaterial-5-yl)methanol.

1H-NMR [CDCl3/TMS δ (ppm)]: 8,80 (1H, s), to 4.81 (2H, s), 4,59 (2H, HF), 2,28 (1H, ush.), to 1.48 (3H, t).

<Reference example 56>

Getting 5-chloromethyl-4-methoxy-6-cryptomaterial

To a solution of 0.42 g (2.02 mmol) of (4-methoxy-6-cryptomaterial-5-yl)methanol at room temperature is added 1.19 g (10.1 mmol) of thionyl chloride. The mixture is stirred for 3 hours for reaction. After confirming completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the contained rest is ritala, obtain 0.45 g (yield quantitative) 5-chloromethyl-4-methoxy-6-cryptomaterial.

<Reference example 57>

Getting 5-methyl bromide-4-ethoxy-6-cryptomaterial

A solution of 3.77 g (17,0 mmol) (4-ethoxy-6-cryptomaterial-5-yl)methanol in 50 ml of diethyl ether cooled to 0°C. To the solution was added 2.0 g (7.2 mmol) of tribromide phosphorus. The mixture is stirred at room temperature for 1 hour. The obtained salt is dissolved using methanol. The resulting mixture was stirred for 1 hour for reaction. The reaction mixture is poured into water, then extracted with diethyl ether. The obtained organic layer was washed with aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain crude 5-methyl bromide-4-ethoxy-6-cryptomaterial.

1H-NMR [CDCl3/TMS δ (ppm)]: 8,79 (1H, s), br4.61 (2H, HF), 4,55 (2H, s), for 1.49 (3H, t).

<Reference example 58>

Receive (2-chloro-4-methylpyridin-3-yl)methanol

A solution of 1.9 g (10.0 mmol) of methyl 2-chloro-4-methylnicotinate in 5.0 ml THF at temperatures from -65 to -60°gradually add to the suspension of 0.4 g (10.0 mmol) of sociallyengaged in 30 ml of tetrahydrofuran. The mixture is stirred for 30 min at -20°C for 1 hour for reaction. Rea the operating mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel, to obtain 0.6 g (yield: 38,2%) (2-chloro-4-methylpyridin-3-yl)methanol.

1H-NMR [CDCl3/TMS δ (ppm)]: 8,19 (1H, d), was 7.08 (1H, d), is 4.85 (2H, s), 2.49 USD (3H, s)

<Reference example 59>

Obtaining 3-acetyl-4-chloromethyl-2,5-dichlorothiophene

To a solution of 5.0 g (32,4 mmol) of 3-acetyl-2,5-dichlorothiophene in 26 ml (323,0 mmol) chloromethylmethylether ether is added dropwise at 10°under ice cooling 33 ml of titanium tetrachloride (2 mol/l dichloromethane solution). The mixture is stirred at room temperature for 2 hours for reaction. Upon completion of the reaction, the reaction mixture was poured into water, then extracted with chloroform. The obtained organic layer is washed with sodium bicarbonate, water and an aqueous solution of sodium chloride in that order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent GE the San the ethyl acetate, 9/1)obtain 2.6 g (yield of 39.7%) of 3-acetyl-4-chloromethyl-2,5-dichlorothiophene in the form of yellow crystals.

1H-NMR [CDCl3/TMS δ (ppm)]: 4,70 (2H, s), of 2.56 (3H, s)to 2.54 (3H, s), 2,39 (3H, s).

<Reference example 60>

Obtain 3-bromo-2-bromomethylpropane

To a solution of 2.8 g (13.3 mmol) of 3-bromo-2-methylbenzofuran in 30 ml of monochlorobenzene added 2.7 g of 15.3 mmol) of N-bromosuccinimide and 0.4 g (2.7 mmol) of azobisisobutyronitrile. The mixture was stirred at 80°C for 30 min for the reaction. After confirmation of the transformation of the original substances, the reaction mixture was cooled to room temperature. The insoluble matter is filtered off. The filtrate is subjected to vacuum distillation to remove the contained solvent. The residue was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent, obtain 3.0 g (yield 79,0%) of 3-bromo-2-bromomethylpropane.

<Reference example 61>

Getting ethyl-1-deformity-1H-pyrazole-4-carboxylate

To a solution of 3.0 g (21,4 mmol) ethyl-1H-pyrazole-4-carboxylate in 100 ml of N,N-dimethylformamide added 6.0 g (of 43.5 mmol) of anhydrous potassium carbonate. Through the MCA is ü bubbled Chlorodifluoromethane. The resulting mixture is stirred at a temperature of from 130 to 140°C for 3 hours for reaction. After confirming completion of the reaction the mixture was poured into water, then extracted with ethyl acetate. The obtained organic layer was washed with water and aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the contained solvent. The residue is purified column chromatography on silica gel (manifesting solvent: mixed solvent of hexane - ethyl acetate), receive a rate of 1.67 g (yield of 41.0%) ethyl-1-deformity-1H-pyrazole-4-carboxylate as a colorless transparent oily substance.

1H-NMR [CDCl3/TMS δ (ppm)]: 8,32 (1H, s), of 8.04 (1H, s), 7,20 (1H, t), 4,32 (2H, HF), to 1.37 (3H, t).

The herbicide of the present invention as the active ingredient contains a derivative of isoxazoline represented by the General formula [I]or its salt.

When using the compounds of the present invention as a herbicide present compound can be used in pure form. Also it can be used in the form of powder, wettable powder, emulsifiable concentrate, liquid form, fine granules, granules, etc. by mixing with a carrier, a surface-active agent, a dispersant, adjuvant and so on, commonly used in the drug.

As the carrier used in the preparation include, for example, solid carriers such as talc, bentonite, clay, kaolin, diatomaceous earth, white carbon, vermiculite, calcium carbonate, slaked lime, silica sand, ammonium sulfate, urea, etc. and liquid media, such as isopropyl alcohol, xylene, cyclohexane, methylnaphthalene, etc.

As the surfactant and dispersant include, for example, metal salts and alkylbenzenesulfonic acid, metal salts and dinaftiletilena acids, salts of sulfates of alcohols, salts alkylarylsulfonate acids, salts ligninsulfonate acid, polyoxyethyleneglycol ether, polyoxyethyleneglycol ethers, monoalkylated of polyoxyethylenesorbitan etc. adjuvant can lead, for example, carboxymethylcellulose, polyethylene glycol and the Arabian gum. When applying the herbicide of the present invention is diluted to the appropriate concentration and carry out spraying or direct application.

The herbicide of the present invention can be used by spraying foliage, soil, drawing on the water surface, etc. the Amount of active ingredient is determined appropriately so that it sootvetstvovali application. The content of active ingredient is determined in accordance with the intended application. When the compound of the present invention prepared in the form of powder or granules, the content is in the range from 0.01 to 10 wt.%, preferably from 0.05 to 5 wt.%. When this connection is made in the form of an emulsifiable concentrate or wettable powder, quantity, respectively, is in the range from 1 to 50 wt.%, from 5 to 30 wt.%. When this connection is made in the form of a fluid medication, and its quantity is respectively in the range from 1 to 40 wt.%, preferably from 5 to 30 wt.%.

The used amount of the herbicide of the present invention varies depending on the type of connection, destroy weeds, and a tendency to germinate weed, environmental conditions, the type of herbicide, etc. When this herbicide is used in pure form in the form of powder or granules, quantity, respectively, is selected in the range from 1 g to 50 kg, preferably from 10 g to 10 kg per 1 hectare is based on the active ingredient. When the herbicide is used in liquid form, as in the case of emulsifiable concentrate, wettable powder or flowable preparation, number, respectively, is selected in the range from 0.1 to 50,000 ppm, preferably from 10 to 10000 h/million

Connect the s of the present invention can be mixed, if necessary, insecticide, fungicide, another herbicide, plant growth regulator, fertilizer, etc.

Below using typical examples preparative forms described preparative form compounds of the present invention. The types of compounds and additives and their ratio is not limited to the following and may vary within wide limits. In the description below, "parts" are by mass parts.

<preparative form 1>

Wettable powder

Mix 10 parts of the compound (3-0006) with 0.5 parts polyoxyethyleneglycol ether, 0.5 parts of a condensate of sodium salt of β-naphtalenesulfonic acid and formalin, 20 parts of diatomaceous earth and 69 parts of clay. The mixture is stirred and sprayed receive a wettable powder.

<preparative form 2>

Fluid drug

In 69 parts of water was dispersed 20 parts roughly chopped connection (3-0006). To the mixture is added 4 parts of sulphate polyoxyethyleneglycol ether, 7 parts of ethylene glycol and 200 ppm based on the received herbicide Silicone AF-118N (the product of the company Asahi Chemical Industry, Co. Ltd.). The resulting mixture was stirred for 30 minutes using a high speed mixer and then milled using a mill, get a fluid drug.

<preparative form 3>

Emulsion

To 30 parts of the compound (3-0006) DOB is given in 60 parts of a mixture of equal volumes of xylene and isophorone and 10 parts of a mixture of surfactants alkylate of polyoxyethylenesorbitan, polyoxyethyleneglycol polymer and alkylarylsulfonate. The resulting mixture was well stirred, get emulsifiable concentrate.

<preparative form 4>

Granules

Mix 10 parts of the compound (3-0006), 80 parts of filler, which is a mixture of 1:3 talc and bentonite, 5 parts of white carbon black and 5 parts of a mixture of surfactants alkylate of polyoxyethylenesorbitan, polyoxyethyleneglycol polymer and alkylarylsulfonate. To the mixture is added 10 parts of water. The resulting mixture was well stirred to a paste. Pasta ekstragiruyut through cell (diameter 0.7 mm) sieve. The extrudate is dried and cut into a length of from 0.5 to 1 mm to obtain pellets.

The following describes examples of the application of the compounds of the present invention, in order to show the effectiveness of the connection.

<Example 1>

Tests of herbicide activity in soil processing flooded fields

Soil flooded fields are filled plastic pots at 100 cm2and tamped. Then sow the seeds of Echinochloa oryzicola Vasing and Monochoria vaginalis (Murm. F.) Presl var. plantaginea (Roxb.) Solms-Laub, and pots filled with water depth of 3 see the next day wettable powders obtained in accordance with example formulation 1, diluted with water and put drops on the surface of the water. The used amount of each of SMAC is a misleading description of the powder is 1000 g/ha based on the active ingredient. Then landing put in the greenhouse and the effect of each herbicide wettable powder assessed at 21 days after treatment in accordance with the standard shown in table 21. The results obtained are presented in table 22.

Table 21
IndexHerbicide effect (the degree of inhibition of growth)

or phytotoxicity
5Herbicide effect or phytotoxicity 90%
4Herbicide effect or phytotoxicity from 70 to

less than 90%
3Herbicide effect or phytotoxicity from 50 to

less than 70%
2Herbicide effect or phytotoxicity from 30 to

less than 50%
1Herbicide effect or phytotoxicity from 10 to

less than 30%
0Herbicide effect or phytotoxicity from 0 to

less than 10%

Table 22

<application Example 2>

Tests of herbicide activity soil handling upland fields

The upland soil p is La filled plastic pots with a surface of 80 cm 2. Then sow the seeds of Echinochloa crus-galli (L) Beauv. var. crus-galli and Setaria viridis (L.) Beauv., then cover the same ground. Wettable powders obtained in accordance with example formulation 1, diluted with water and sprinkle evenly on the soil surface using a small sprayer in quantities of 1000 l/ha, so the amount of each active ingredient is 1000 g/ha Then landing put in the greenhouse and the effect of each herbicide wettable powder assessed at 21 days after treatment in accordance with the standard shown in table 21. The results obtained are presented in table 23.

Table 23

<application Example 3>

Tests of herbicide activity during the processing of the leaves of terrestrial plants

Fill with sand plastic pots with a surface of 80 cm2. Sow the seeds of Echinochloa crus-galli (L.) Beauv. var. crus-galli and Setaria viridis (L.) Beauv. Landing kept in the greenhouse for 2 weeks. Wettable powders obtained in accordance with example formulation 1, diluted with water and sprinkle evenly on the entire foliage of the plants using a small sprayer in quantities of 1000 l/ha, so the amount of each active ing is edient is 1000 g per hectare. Then landing put in the greenhouse and the effect of each herbicide wettable powder assessed on day 14 after treatment in accordance with the standard shown in table 21. The results obtained are presented in table 24.

Table 24

Industrial applicability

The compound represented by the formula [I] in accordance with the present invention shows the excellent herbicide action over a wide period, from time to germination until active growth of various weeds that cause problems in dry fields, such as broad-leaved weeds [e.g., Polygonum lapathifolium L. subsp. nodosum (Pers.) Kitam., Amaranthus viridis L., Chenopodium album L., Stellaria media (L.) Villars, Abutilon theophrasti Medik., Sida spinosa, Sesbaria exaltata, Ipomea spp. and Xanthium strumarium L.], perennial or annual ookinete weeds [e.g., Cyperus rotundus L., Cyperus esculentus, Kyllinga brevifolia Rottb. subsp. leiolepis (Fraxch. et Savat.) T. Koyama, Cyperus microiria Steud. and Cyperus iria L.] and grassy weeds [e.g., Echinochloa crus-galli (L.) Beauv. var. crus-galli, Digitaris ciliaris (Retz) Koeler, Setaria viridis (L.) Beauv., Poa annua L., Sorghum halepense (L.) Pers., Alopecurus aequalis Sobol var. amurensis (Komar.) Ohwi and Avena fatua L.]. In addition, the compound of the present invention also has a herbicide effects on weeds growing in flooded fields, i.e. annual weeds [e.g., Echinochloa oryzicola Vasing., Cyperus difformis L., Monochoia vaginalis (Burm. F.) Presl var. plantaginea (Roxb.) Solms-Laub. and Lindernia procumbens] and perennial weeds [for example, Sagittaria trifolia L., Sagittaria pygmaea Mig., Cyperus serotinus Rottb., Eleocharis kuroguwai Ohwi and Scirpus juncoides Roxb. subsp. hotarui (Ohwi) T. Koyama, Alisma canaliculatum].

The herbicide of the present invention has high safety for crops, particularly rice, wheat, barley, maize, sorghum, soybean, cotton, sugar beet, etc.

1. Derived isoxazoline represented by the following General formula [I]or its pharmaceutically acceptable salt

where R1and R2may be the same or different and each represents a C1-C10-alkyl group;

R3and R4each represents a hydrogen atom;

R5and R6may be the same or different and each represents a hydrogen atom or C1-C10-alkyl group;

Y is a 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group containing one or more heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, and the heterocyclic group may be substituted by 0 to 6 identical or different groups selected from the following group of substituents α; when the heterocyclic group is substituted in two adjacent positions by two al the ilen groups, alkyl group and alkoxygroup, all of which are selected from the group of substituents α, two groups can form together with the atoms to which they are linked, 5-8-membered ring which may be substituted by 1-4 halogen atoms; heteroatom of the heterocyclic group, when it represents a nitrogen atom may be oxidized to N-oxide;

n takes on integer values from 0 to 2;

[group Vice α]:

hydroxyl group; halogen atoms; C1-C10-alkyl groups; C1-C10-alkyl groups, each of which monogamist group selected from the following group of substituents β; C1-C4-halogenoalkane group; C3-C8-cycloalkyl group; C1-C10-alkoxygroup; C1-C10-alkoxygroup, each of which monogamist group selected from the following group of substituents γ; C1-C4-halogenlampe; C3-C8-cycloalkylcarbonyl; C3-C8-cycloalkyl-C1-C3-alkoxygroup; C1-C10-allylthiourea; C1-C10-allylthiourea, each of which monogamist group selected from the following group of substituents; C2-C6-alkeline group; C2-C6-alkenylacyl; C2-C6-alkyline group; C2-C6-alkyloxy; C1-C10-alkylsulfonyl group; optionally substituted phenyl group; optionally substituted fenoxaprop; optionally substituted aromatic heterocyclic group; not necessarily Thames is installed phenylsulfonyl group; acyl groups; C1-C10-alkoxycarbonyl group; cyano; carnemolla group (its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups and optionally substituted phenyl groups); C1-C6-alloctype; and the amino group (its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups);

[group Vice β]:

hydroxyl group; C3-C8-cycloalkyl group which may be substituted by a halogen atom or alkyl group; C1-C10-alkoxygroup; C1-C10-allylthiourea; C1-C10-alkylsulfonyl group; C1-C10-alkoxycarbonyl group; amino group; carnemolla group (its nitrogen atom may be substituted by identical or different C1-C10-alkyl groups; C1-C6-acyl groups; C1-C10-alkoxyimino; cyano; optionally substituted phenyl group;

[group Vice γ]:

optionally substituted phenyl group; optionally substituted aromatic heterocyclic group; cyano.

2. Derived isoxazoline according to claim 1, where the group of substituents α heterocycle which may be substituted by 0 to 6 identical or different groups include a hydroxyl group; halogen atoms; C1-C10-alkyl groups; C1-C10-alkyl group, each and what are monogamist group, selected from the group of substituents β; C1-C4-halogenoalkane group; C3-C8-cycloalkyl group; C1-C10-alkoxygroup; C1-C10-alkoxygroup, each of which monogamist group selected from the group of substituents γ; C1-C4-halogenlampe; C3-C8-cycloalkylcarbonyl; C3-C8-cycloalkyl-C1-C3-alkyloxy; C1-C10-allylthiourea; C1-C10-allylthiourea, each of which monogamist group selected from the group of substituents γ; C2-C6-alkeline group; C2-C6-alkenylacyl; C2-C6-alkyline group; C2-C6-alkyloxy; C1-C10-alkylsulfonyl group; optionally substituted phenyl group; optionally substituted by fenoxaprop; optionally substituted phenylsulfonyl group; optionally substituted aromatic heterocyclic group; C1-C6-acyl groups; C1-C10-alkoxycarbonyl group; a cyano; karbamoilnuyu group (its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups and optionally substituted phenyl group); and the amino group (its nitrogen atom may be substituted by identical or different groups selected from C1-C10-alkyl groups); when the heterocyclic group is substituted in two adjacent positions by two alkyl groups, the alkyl group and alkoxygroup, all of which are selected from the group sweep the oil α two groups can form together with the atoms to which they are linked, 5-8-membered ring which may be substituted by 1-4 halogen atoms.

3. Derived isoxazoline according to claim 2, where the group of substituents α heterocycle which may be substituted by 0 to 6 identical or different groups include halogen atoms; C1-C10-alkyl groups; C1-C4-halogenoalkane group; C1-C10-alkoxy-C1-C3-alkyl groups; C3-C8-cycloalkyl group; C1-C10-alkoxygroup; C1-C4-halogenlampe; C3-C8-cycloalkyl-C1-C3-alkyloxy; optional substituted fenoxaprop; C1-C10-allylthiourea; C1-C10-alkylsulfonyl groups; acyl groups; C1-C10-alkoxycarbonyl group; a cyano and karbamoilnuyu group (its nitrogen atom may be substituted by identical or different C1-C10-alkyl groups).

4. Derived isoxazoline according to any one of claims 1, 2 or 3, where the substituents R1and R2may be the same or different and each represents methyl group or ethyl group; each of the substituents R3, R4, R5and R6represents a hydrogen atom.

5. Derived isoxazoline according to any one of claims 1, 2, 3 or 4, where Y represents a 5 - or 6-membered aromatic heterocyclic group containing a heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom.

6. Production is circa isoxazoline according to claim 5, where Y represents a thienyl group, pyrazolidine group, isoxazolyl group, isothiazolinone group, pyridyloxy group or pyramidalnou group.

7. Derived isoxazoline according to claim 6, where Y is thiophene-3-ilen group, pyrazole-4-ilen group, a pyrazole-5-ilen group, isoxazol-4-ilen group, isothiazol-4-ilen group, pyridine-3-ilen group, or pyrimidine-5-ilen group.

8. Derived isoxazoline according to claim 7, where Y is thiophene-3-ilen group and a thiophene ring at positions 2 and 4 substituted by the Deputy from the group of substituents α.

9. Derived isoxazoline according to claim 7, where Y is a pyrazole-4-ilen group and the pyrazol ring substituted in positions 3 and 5 Deputy from the group of substituents αand in position 1 is hydrogen atom, C1-C10-alkyl group, C1-C10-alkyl group monosubstituted by a group selected from the group of substituents β, C1-C4-halogenoalkanes group, C3-C8-cycloalkyl group, C2-C6-alkenylphenol group, C2-C6-alkenylphenol group, C1-C10-alkylsulfonyl group optionally substituted phenyl group, optionally substituted aromatic heterocyclic group, optionally substituted phenylsulfonyl group, acyl group, optionally substituted bentilee group, C1-C10-alkoxycarbonyl group./p>

10. Derived isoxazoline according to claim 7, where Y is a pyrazole-5-ilen group and the pyrazol ring substituted in position 4 by a Deputy from the group of substituents αand in position 1 - C1-C4-halogenoalkanes group optionally substituted phenyl group.

11. Derived isoxazoline according to claim 7, where Y is isoxazol-4-ilen group and isoxazoline ring substituted in positions 3 and 5 Deputy from the group of substituents α.

12. Derived isoxazoline according to claim 7, where Y is isothiazol-4-ilen group, isothiazol ring substituted in positions 3 and 5 Deputy from the group of substituents α.

13. Derived isoxazoline according to claim 7, where Y is a pyridine-3-ilen group and the pyridine ring is substituted in positions 2 and 4 Deputy from the group of substituents α.

14. Derived isoxazoline according to claim 7, where Y is a pyrimidine-5-ilen group, and a pyrimidine ring substituted in positions 4 and 6 Deputy from the group of substituents α.

15. Derived isoxazoline according to any one of claims 1 to 14, where n is equal to 2.

16. Derived isoxazoline according to any one of claims 1 to 14, where n is equal to 1.

17. Derived isoxazoline according to any one of claims 1 to 14, where n is equal to 0.

18. A herbicide containing as an active ingredient derived isoxazoline presented in any one of claims 1 to 17, or f is matemticas acceptable salt.



 

Same patents:

FIELD: organic chemistry.

SUBSTANCE: invention relates to new 2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydroxytiazolo[5,4-b]indole of formula useful in liver protection from poisoning with carbon tetrachloride. Said compound has boiling point of 174-175°C (decomposition) and LD50 of 1950±180 mg/kg. Method for production of claimed compound also is disclosed.

EFFECT: new compound for liver protection from poisoning with carbon tetrachloride.

2 ex, 1 tbl

FIELD: organic chemistry, medicine, pulmonology.

SUBSTANCE: invention relates to a new chemical compound, namely, 7-bromo-4-acetylthiazolo[5,4-b]indol-2-succinimide of the formula: that is able to protect body against hypoxia and possesses the curative effect in lung toxic edema. The melting point of this compound is 267-269°.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry, medicine, pulmonology.

SUBSTANCE: invention relates to a new chemical substance, namely, 4-acetylthiazolo[5,4-b]indol-2-succinimide of the formula: that is able to protect body against hypoxia and possesses the prophylactic effect in lung toxic edema. The melting point of this substance is 264-265°C.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a new 2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydrothiazolo[5,4-b]indole hydrobromide of the formula (1) that is able to protect body against hypoxia and liver against poisoning with carbon tetrachloride. The melting point of this compound is 266-267°C (with decomposition). The compound is synthesized from 1-acetyl-5-bromo-3-indolinone and elemental bromine in dioxane medium followed by addition of thiourea in isopropyl alcohol.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

EFFECT: improved preparing method, valuable biological and medicinal properties of compounds and pharmaceutical composition.

15 cl, 5 tbl, 6 ex

FIELD: medicine, pharmacology, organic chemistry.

SUBSTANCE: invention relates to using 2-amino-4-acetyl-8b-hydroxy-3a,8b-dihydrothiazole[5,4-d]indole as a substance protecting body against hypoxia effect. Invention provides enhanced effectiveness of the protection effect.

EFFECT: enhanced effectiveness of effect of agent.

1 tbl, 1 ex

FIELD: medicine, pharmacology, organic chemistry.

SUBSTANCE: invention relates to using 2-amino-4-acetylthiazolo[5,4-d]indole for protection of body against effect of hemic and hypercapnic hypoxia. Invention proves high effectiveness of the protection effect.

EFFECT: enhanced effectiveness of agent.

2 tbl

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds comprising 2-aminopyridin-3-sulfonic fragment of the general formula (1) or their pharmaceutically acceptable salts, N-oxides or hydrates possessing properties of antagonists of glutamate-induced calcium ions transport, in particular, neuroprotective effect. Also, invention relates to the focused library for the search of biologically active leader-compounds comprising at least one heterocyclic compound of the general formula (1) and to pharmaceutical composition if form of tablets, capsules or injections placed into pharmaceutically acceptable package containing compounds of invention as an active substance. In compound of the general formula (1) R1 represents hydrogen atom; R2 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; or R1 and R2 in common with nitrogen and sulfur atoms to which they are bound form optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazabenzocyclohepten-8-one. Also, invention discloses methods for preparing different compounds of the general formula (1).

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

10 cl, 4 sch, 4 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using phenylethenyl- or phenylethynyl-derivatives as antagonists of glutamates receptors. Invention describes using compound of the general formula (I):

wherein each among R1, R2, R3, R4 and R5 means independently of one another hydrogen atom, (C1-C6)-alkyl, -(CH2)n-halogen, (C1-C6)-alkoxy-group, -(CH2)n-NRR', -(CH2)n-N(R)-C(O)-C1-C6)-alkyl, phenyl or pyrrolyl that can be unsubstituted or substituted with one or more (C1-C6)-alkyl; each among R, R' and R'' means independently of one another hydrogen atom or (C1-C6)-alkyl; A means -CH=CH- or C≡C; B means ,, , , or wherein R6 means hydrogen atom, (C1-C)-alkyl, -(CH2)n-C(O)OR, or halogen atom; R7 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-C(O)OR', halogen atom, nitro-group or oxodiazolyl group that can be unsubstituted or substituted with (C1-C6)-alkyl or cycloalkyl; R8 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-OH, -(CH2)n-C(O)OR'' or phenyl; R9 means (C1-C6)-alkyl; R10 and R11 mean hydrogen atom; R12 means -(CH2)n-N(R)-C(O)-(C1-C6)-alkyl; R13 means hydrogen atom; each R14, R15, R16 and R17 independently of one another means hydrogen atom or (C1-C6)-alkoxy-group; each R18, R19 and R20 independently of one another means hydrogen atom; R21 means hydrogen atom or (C1-C6)-alkyl; R22 means hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkyl comprising one or more substitutes chosen from groups hydroxy- or halogen atom; R23 means hydrogen atom, (C1-C6)-alkanoyl or nitro-group; each among R24, R25 and R26 independently of one another means hydrogen atom or (C1-C6)-alkyl; n = 0, 1, 2, 3, 4, 5 or 6; X means -O- or -S-; Y means -CH= or -N=, and its pharmaceutically acceptable salts used in preparing medicinal agents designates for treatment or prophylaxis of disorders mediated by mGluR5-receptors. Also, invention describes compounds of the formula (I-A), compound of the formula (I-B-1) given in the invention description, and a medicinal agent used in treatment or prophylaxis of disorders mediated by mGluR5-receptors.

EFFECT: valuable medicinal properties of compounds.

44 cl, 1 tbl, 44 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

EFFECT: improved preparing method, valuable biological and medicinal properties of compounds and pharmaceutical composition.

15 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzoxazepine and describes derivative of benzoxazepine of the general formula (I): wherein X represents -CO or -SO2; R1, R2, R3 and R4 are chosen independently from hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkyloxy-(C1-C4)-alkyl, -CF3, halogen atom, nitro-group, cyano-group, -NR8R9, -NR8COR10 and -CONR8R9; R5, R6 and R7 represent independently hydrogen atom (H) or (C1-C4)-alkyl; R8 and R9 represent independently hydrogen atom (H) or (C1-C4)-alkyl; or R8 and R9 in common with nitrogen atom to which they are bound form 5- or 6-membered saturated heterocyclic ring comprising optionally the additional heteroatom chosen from oxygen atom (O), sulfur atom (S) or the group -NR11; R10 represents (C1-C4)-alkyl; R11 represents (C1-C4)-alkyl; A represents residue of 4-7-membered saturated heterocyclic ring comprising optionally oxygen atom wherein ring is substituted optionally with 1-3 substitutes chosen from (C1-C4)-alkyl, (C1-C4)-alkoxy-, hydroxy-group, halogen atom and oxo-group, or to its pharmaceutically acceptable salt under condition that compounds of the formula (I) are excluded wherein X represents -CO, and each among R1-R7 represents hydrogen atom (H), and A represents -(CH2)3 or -(CH2)4; compounds of the formula (I) wherein X represents -CO; R1 represents hydrogen atom (H); R2 represents methyl (CH3); each among R3-R7 represents hydrogen atom (H), and A represents -(CH2)3; compounds of the formula (I) wherein X represents -CO; R1 and R2 represent hydrogen atom (H); R3 represents methyl; each among R4-R7 represents hydrogen atom (H), and A represents -(CH2)3; compounds of the formula (I) wherein X represents -CO; each among R1-R3 represents hydrogen atom (H); R4 represents methyl; each among R5-R7 represents hydrogen atom (H), and A represents -(CH2)3, and compounds of the formula (I) wherein X represents -CO; each among R1-R4 represents hydrogen atom (H); R5 represents methyl; R6 and R7 represent hydrogen atom (H), and A represents -(CH2)3. Also, invention describes pharmaceutical compositions comprising indicated derivatives and using these benzoxazepine derivatives in treatment of neurological diseases and psychotic disorders sensitive to enhancing responses mediated by AMPA receptors in the central nervous system. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new amide derivatives of carboxylic acid that are antagonists of NMDA receptors of the formula (I): , wherein one radical among R1, R2, R3 and R4 represents -OH or NH2-group and others are hydrogen atoms; or two adjacent groups R1, R2, R3 and R4 in this case in common with one or more similar or different additional heteroatoms and -CH= and/or -CH2-groups form 5-6-membvered homo- or heterocyclic ring but preferably pyrrole, pyrazole, imidazole, oxazole, oxooxazolidine or 3-oxo-1,4-oxazine ring; two other groups among R1, R2, R3 and R4 radicals represent hydrogen atoms; R5 and R6 in common with nitrogen atom between them form saturated or unsaturated 4-6-membered heterocyclic ring that is substituted with phenoxy-, phenyl-[(C1-C4)-alkoxy]-, phenoxy-[(C1-C4)-alkyl]-, benzoyl-group optionally substituted in aromatic ring with one or more halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; X and Y mean independently oxygen, nitrogen atom or group -CH=, and to their salts formed with acids and bases. Also, invention relates to a method for preparing compounds of the formula (I) and pharmaceutical compositions showing activity as selective antagonists of NR2B receptor based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of the following diseases: chronic neurodegenerative diseases, chronic painful states, bacterial and viral infections.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

11 cl, 2 tbl, 27 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacology.

SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of gyrase.

54 cl, 5 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

FIELD: chemical industry; method of production of the fluorine-containing compounds.

SUBSTANCE: the invention is pertaining to the chemical industry, in particular, to the improved method of production of fluorine-containing compounds from the halogen-containing, compounds, preferably, from chlorine-containing compounds due to an exchange of halogen for fluorine at presence of the HF-additional compound of the mono- or bicyclic amine with at least two atoms of nitrogen. At that at least one atom of nitrogen is built in the cyclic system as the fluorating agent; or at presence of anhydrous hydrogen fluoride - as the fluorating agent and the indicated HF-additional compound of the mono- or bicyclic amine as the catalyst. At usage of the applicable solvents the reaction mixtures can be divided into two phases and thus to simplify the reprocessing of the products. The invention also is pertaining to the HF-additional compounds of 1.5-diazabicyclo[4.3.0]non-5-en and N,N-dialkylaminopiridin, where alkyl represents C1-C4alkyl and where the molar ratio of HF to amine makes 1:1, and to HF- additional compounds 1.8- diazabicyclo[5.4.0]undecyl-7-ene, where the molar ratio of HF to amine compounds more than 1:1.

EFFECT: the invention ensures at usage of the applicable solvents to divide the reaction mixture into two phases and thus to simplify reprocessing of the products.

17 cl, 13 ex

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