Substituted dihydro-3-halogen-1h-pyrazol-5-carboxylates, their preparing and using

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 represents halogen atom; R2 represents halogen atom; R3 represents (C1-C4)-alkyl; X represents nitrogen atom (N) or -CH; n = 0-3 under condition that when X represents -CH then n= 1 at least. Also, invention relates to novel compounds of the formula (II): wherein R1 represents halogen atom; R2 represents halogen atom; R3 represents hydrogen atom (H) or (C1-C4)-alkyl; X represents N or -CH; n = 0-3 under condition that when X represents -CH then n = 1 at least. Also, invention relates to a method for synthesis of compound of the formula (I), a method for synthesis of compound of the formula (II) and to a method for synthesis of compound of the formula (III) given in the invention description. Also, invention describes intermediate compounds of the formula (4) given in the invention description. Invention provides synthesis of novel biologically active compounds that can be used as insecticides, and a method for their synthesis.

EFFECT: valuable properties of compounds.

24 cl, 3 tbl, 19 ex

 

The SCOPE of the INVENTION

The present invention relates to new compounds of 3-halogen-1-aryl-substituted dihydro-1H-pyrazoles and pyrazoles based on carboxylic acids. These compounds are suitable for the production of certain compounds on the basis of antranig-amides, which are of interest as insecticides (see, for example, PCT publication WO 01/070671).

BACKGROUND of the INVENTION

Tetrahedron Letters, 1999, 40, 2605-2606 describes the formation of compounds 1-phenyl-3-bromopyrazole-5-carboxylic acids, including the production of reactive intermediate compounds branitelja. The cycloaddition reaction of this intermediate with complex acrylic ester gives a complex 1-phenyl-3-bromo-2-pyrazolin-5-carboxylate ester, which can then be oxidized to the desired complex of 1-phenyl-3-bromo-2-pyrazole-5-carboxylate ester. Alternatively, the cycloaddition of ester propiolate directly gives a complex 1-phenyl-3-bromo-2-pyrazole-5-carboxylate ester.

U.S. patent 3153654 describes the condensation of certain optionally substituted aryl (e.g. phenyl or naphthyl, which are optionally substituted lower alkyl, lower alkoxy or halogen) hydrazines with certain complex fumaric or maleic esters, to obtain the derivatives of 3-pyrazolidinone carboxylic acids.

Publicat and non-examination of the Japan patent 9-316055 and 9-176124 describe obtaining compounds of peratrovich esters of carboxylic acids and derivatives pyrazolines, respectively, which are substituted by alkyl in the 1-position.

J. Med. Chem. 2001, 44, 566-578 describes how to obtain 1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid and its use in obtaining inhibitors of coagulation factor Xa.

The present invention provides methods, suitable for convenient preparation of 3-halogen-5-carboxylate-1-aryl-substituted dihydro-1H-pyrazoles and pyrazoles.

BRIEF description of the INVENTION

The present invention relates to a compound of formula I

where

R1is a halogen;

each R2represents, independently, With1-C4alkyl, C2-C4alkenyl,2-C4quinil, C3-C6cycloalkyl, C1-C4halogenated,2-C4halogenoalkanes,2-C4halogenoalkanes, C3-C6halogenosilanes, halogen, CN, NO2C1-C4alkoxy, C1-C4halogenoalkane, C1-C4alkylthio, C1-C4alkylsulfonyl, C1-C4alkylsulfonyl, C1-C4alkylamino, C2-C8dialkylamino, C3-C6cyclooctylamino, C3-C6(alkyl)cyclooctylamino,2-C4alkylsulphonyl, C2-C6alkoxycarbonyl, C2-C6alkylaminocarbonyl, C3-C8dialkylamino is carbonyl or C 3-C6trialkylsilyl;

R3represents H or C1-C4alkyl;

X represents N or CR4;

R4represents H or R2; and

n is from 0 to 3, provided that when X represents CH, n is at least 1.

The present invention also relates to a method for obtaining compounds of formula I, including (1) treatment of compounds of formula 4

(where X, R2and n are as described above for formula I, and R3represents a C1-C4alkyl) halogenation agent, for obtaining the compounds of formula I; and then, in the case of preparing compounds of formula I, where R3represents H, (2) converting the compound obtained in (1) in connection, where R3represents H.

The present invention also relates to the compound of formula II

where R1represents a halogen (and X, R2, R3and n are as defined above for formula (I), and to a method for obtaining compounds of formula II. The method includes (3) treatment of compounds of formula I of oxidant optionally in the presence of acid to obtain the compounds of formula II; and when the compound of formula I, where R3represents a C1-C4alkyl, is used for gaining the compounds of formula II, where R3represents H, (4) converting the compound obtained in (2), the compound of formula II, where R3represents H.

The present invention also provides compounds of formula 4 where X represents N, and their use in the formation of compounds of formulas I and II, where X is a N (and R2, R3and n are as defined above for formula (I).

The present invention also includes a method of obtaining the compounds of formula III

where X, R1, R2and n are as defined above for formula II; R6represents CH3, Cl or Br; R7represents F, Cl, Br, I or CF3; and R8represents a C1-C4alkyl, with the use of the compounds of formula II, where R6represents H. This method is obtaining the compounds of formula II using the method as described above.

DETAILED description of the INVENTION

In the above enumeration, the term "alkyl", used either by itself, or in compound words such as "alkylthio" or "halogenated"includes alkyl straight or branched chain such as methyl, ethyl, n-propyl, ISO-propyl, or the different butyl isomers, pentile or exile. "Alkenyl may include alkenes with a straight or branched chain, such as 1-p is openil, 2-propenyl, and various isomers butenyl, pentenyl and hexenyl. "Alkenyl also includes a polyene, such as 1,2-PROPADIENE and 2,4-hexadienyl. "Quinil includes alkynes with a straight or branched chain, such as 1-PROPYNYL, 2-PROPYNYL, and the various isomers of butenyl, pentenyl and hexenyl. "Quinil" may also include residues containing many ternary relationships, such as 2,5-hexadienyl. "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropoxy and various isomers of butoxy, pentox, hexyloxy. "Alkoxyalkyl" denotes alkoxy substitution of the alkyl group. Examples of "alkoxyalkyl" include CH3OCH2CH3OCH2CH2CH3CH2OCH2CH3CH2CH2CH2OCH2and CH3CH2OCH2CH2. "Alkylthio" includes alkylthio remains straight or branched chain, such as methylthio, ethylthio, and various isomers of property, butylthio, pentylthio and hexylthio. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "Cycloalkenyl" refers to an alkyl group substituted cycloalkyl group, and includes, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. "Cycloalkenyl" means that the nitrogen atom of the amino attached to cycloalkenes the radical and the hydrogen atom and includes t is the cue group, as cyclopropylamino, cyclobutylamine, cyclopentylamine, cyclohexylamine. "(Alkyl)cyclooctylamino" means cyclooctylamino group where a hydrogen atom is substituted by an alkyl radical; examples include groups such as (alkyl)cyclopropylamino, (alkyl)cyclobutylamine, (alkyl)cyclopentylamine and (alkyl)cyclohexylamine. Preferably, the alkyl (alkyl)cyclooctylamino represents a C1-C4alkyl, while cycloalkyl in cyclooctylamino and (alkyl)cyclooctylamino represents a C3-C6cycloalkyl.

In this application, the term "aryl" refers to aromatic ring, or ring system, or heteroaromatic ring, or ring system, each ring or ring system is optionally substituted. The term "aromatic ring system" denotes fully unsaturated carbocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic. Aromatic indicates that each of the ring atoms is essentially in the same plane and has a p-orbital perpendicular to the plane of the ring, and in which (4n + 2)π electrons, where n is 0 or a positive integer, are associated with the ring, in accordance with the hückel rule. The term "aromatic carbocycles the I ring system" includes fully aromatic carbocycle and carbocycle, in which at least one ring of a polycyclic ring system is aromatic (e.g. phenyl and naphthyl). The term "heteroaromatic ring or ring system" includes fully aromatic heterocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic and in which at least one atom of the ring is carbon and which may contain 1 to 4 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that each heteroaromatic ring contains no more than 4 atoms of nitrogen, not more than 2 oxygen atoms and not more than 2 sulfur atom (where aromatic indicates that is the hückel rule). Heterocyclic ring system may be connected through any available carbon atom or nitrogen by replacement of a hydrogen on the designated atom is carbon or nitrogen. More specifically, the term "aryl" refers to the residue

where R2and n are as defined above, and "3" stands for 3-d position of the substituents on the remainder.

The term "halogen", either by itself or in compound words such as "halogenated"includes fluorine, chlorine, bromine or iodine. In addition, when used in compound words such as "halogen is lcil", the specified alkyl may be partially or completely replaced by halogen atoms that can be the same or different. Examples of "halogenoalkane" include F3C, ClCH2, CF3CH2and CF3CC12. The terms "halogenoalkanes", "halogenoalkanes", "halogenoalkane", and the like, are defined by analogy with the term "halogenated". Examples of "halogenoalkane include (C1)2C = CHCH2and CF3CH2CH = CHCH2. Examples of "halogenoalkane" include HC ≡ CCHCl, CF3C ≡ C, CC13C ≡ C and FCH2C ≡ CCH2. Examples of "halogenoalkane" include CF3O CC13CH2O, HCF2CH2CH2O and CF3CH2O.

Examples of "alkylcarboxylic" include C(O)CH3C(O)CH2CH2CH3and C(O)CH(CH3)2. Examples of "alkoxycarbonyl" include CH3OC(=O), CH3CH2OC(=O), CH3CH2CH2OC(=O) (CH3)2CHOC(=O) and the various isomers of butoxy or phenoxycarbonyl. The terms "alkylaminocarbonyl and dialkylaminoalkyl" include, for example, CH3NHC(=O), CH3CH2NHC(=O) and (CH3)2NC(=O).

The total number of carbon atoms in the group-the Deputy indicated with the prefix "Ci-Cj"where i and j are numbers from 1 to 8. For example, C1-C3alkylsulfonyl designates the connection from methylsulfonyl propylsulfonyl. In the above enumerations, when the compound of formula I contains a heteroaromatic ring, all substituents are connected with the ring through any available carbon atom or nitrogen by replacement of a hydrogen on the designated atom is carbon or nitrogen.

When a group contains a Deputy, who may be a hydrogen, for example, R4when this Deputy is taken as hydrogen, it is obvious that this is equivalent to the fact that the specified group is unsubstituted.

Certain compounds of the present invention can exist as one or more stereoisomers. Different stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. The person skilled in the art should remember that one stereoisomer may be more active and/or may exhibit beneficial effects when enrichment, relative to the other stereoisomer (stereoisomers), or when it is separated from the other stereoisomer (stereoisomers). In addition, the person skilled in the art knows how to select, to increase the content and/or to selectively receive said stereoisomers. Accordingly, the compounds of the present invention may be present in the form of a mixture of stereoisomers, individual stereoisomers, or as optically active forms.

From the point the of view of cost, ease of synthesis and/or greatest usefulness preferred are the following compounds:

1. The compounds of formula I, where R1represents Cl or Br;

each R2represents, independently, Cl or Br, and one of R2is in the 3rd position; and

X represents n

2. The compounds of formula I, where

R1represents Cl or Br;

X represents N; and

n is 0.

Of particular note are the compounds of formula I (including, but not limited to the preferred compounds 1), where n is from 1 to 3.

3. The compounds of formula II, where

X represents n

4. The compounds of formula II, where

R1represents Cl or Br;

each R2represents independently Cl or Br, and one of R2is in the 3rd position; and

X represents n

5. The compounds of formula II, where

R1represents Cl or Br;

X represents N; and

n is 0.

Of particular note are the compounds of formula II (including but not limited to the preferred compounds 3 and 4), where n is from 1 to 3.

6. The compounds of formula 4 (where R3represents a C1-C4alkyl), where each R2represents independently Cl or Br, and one of R2is in the 3rd position.

7. The compounds of formula 4 (where R3represents a C1-C4 alkyl), where

X represents N; and

n is 0.

Of particular note are the compounds of formula 4 (where R3represents a C1-C4alkyl)including, but not limited to the preferred compounds 6, where n is from 1 to 3.

3rd position is determined by the numbers "3", depicted in the aryl residue, included above in formula I, formula II and formula 4.

Especially preferred compounds of formula II, where, when R1represents Cl or Br, n is 1, and R2selected from Cl or Br, is in the 3rd position; then X represents N. Enabled connections, where n is from 1 to 3.

Especially preferred compounds of formula II, where, when R1represents Cl or Br, n is 1, and R2selected from Cl or Br, is in the 3rd position; then X represents CR4. Included compound, where n is from 1 to 3.

Preferred methods are those which contain the preferred compounds mentioned above. Noted how are those which include the compounds mentioned above. Especially noted are the method of obtaining the compounds of formula I, where n is from 1 to 3; and the method of obtaining the compounds of formula II, where n is from 1 to 3.

Multi-stage method of preparing compounds of formula I and formula II, provided here includes (a) is the preparation of compounds of formula 2

the compound of the formula 3

where R3represents a C1-C4alkyl,

in the presence of a base, to obtain the compounds of formula 4

where X, R2and n are as defined above, and R3represents H or C1-C4alkyl.

The compound of formula 4 where R3represents a C1-C4alkyl may then (1) is treated halogenation agent, for obtaining the compounds of formula I; and, in the case of obtaining the compounds of formula I, where R3represents H, and (2) the compound obtained in (1), is converted to the compound, where R3represents H.

The compound of formula I, obtained in (1) or (2), then (3) be processed oxidant, optionally in the presence of acid to obtain the compounds of formula II; and when the compounds of formula I, where R3represents a C1-C4alkyl, are used to obtain compounds of formula II, where R3represents H, (4), carry out the conversion of the compound obtained in (3), the compound of formula II, where R3represents H

Scheme 1 illustrates the stage (a).

Scheme 1

At stage (a), the compound of formula 2 is treated with a compound of formula 3, where R3represents a C1-C4alkyl (can be used for complex or fumaric malaty esters, or a mixture thereof), in the presence of base and solvent. The Foundation, as a rule, is a salt of a metal alkoxide such as sodium methoxide, potassium methoxide, ethoxide sodium, atoxic potassium, tertbutoxide potassium, tertbutoxide lithium, and the like. You must use more than 0.5 equivalent of base, relative to the compound of formula 2, preferably between 0.9 and 1.3 equivalent. You need to use more than 1.0 equivalent of the compound of formula 3, preferably between 1.0 and 1.3 equivalent. Can be used proton polar and polar aprotic organic solvents, such as alcohols, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, and the like. Preferred solvents are alcohols, such as methanol and ethanol. It is especially preferred that the alcohol was the same as that used in obtaining complex fumaric or malatova ether and alkoxides Foundation. Typically, the interaction is carried out by mixing the compounds of formula 2 and the base in the solvent. The mixture may the unit's electric is camping or cooled to the desired temperature, and the compound of formula 3 add for some period of time. Typical reaction temperatures are between 0°C and the boiling point of the used solvent. The interaction may be carried out at a pressure greater than atmospheric pressure to increase the boiling point of the solvent. As a rule, preferred are temperatures in the range approximately between 30° and 90°C. the Time of addition can be as fast as possible with the temperature change (heat transfer). Typical time added is in the range between 1 minute and 2 hours. The optimum reaction temperature and time are added vary depending on the nature of the compounds of formula 2 and formula 3. After the addition, the reaction mixture may be maintained for some time at the reaction temperature. Depending on the reaction temperature, the required aging time may be in the range of from 0 to 2 hours. Typical aging time is about 10 to 60 minutes. Then the reaction mass can be acidified by adding organic acids such as acetic acid, and the like, or inorganic acids such as hydrochloric acid, sulfuric acid, and the like. Depending on the reaction conditions and means of selection, may be the Holocene the compounds of formula 4, where R3represents H, or the compounds of formula 4 where R3represents a C1-C4alkyl. For example, the compound of formula 4 where R3represents a C1-C4alkyl, can be either hydrolyzed in situ to the compounds of formula 4 where R3represents H, when the reaction mixture is water. The compounds of formula 4 where R3represents H, can easily be converted into compounds of formula 4 where R3represents a C1-C4alkyl, using methods of esterification are well known in this field. The compounds of formula 4 where R3represents a C1-C4alkyl, are preferred. The desired product, compound of formula 4 can be selected using methods known to the person skilled in the art, such as crystallization, extraction or distillation.

At the stage (1), as illustrated in scheme 2, the compound of formula 4 is treated using a halogenation reagent, usually in the presence of a solvent. Halogenation reagents that can be used include oxychloride, trihalogen and pentavalent phosphorus, thionyl chloride, dialoginterface, dialoginterface, oxalicacid and phosgene. Preferred are oxychloride and pentavalent phosphorus. the La complete conversion, you must use at least 0.33 equivalent oxychloride phosphorus, relative to the compound of formula 4, preferably in the range of 0.33 and 1.2 equivalent. For complete conversion, you must use at least 0.20 equivalent pentachloride phosphorus in relation to the compound of formula 4, preferably in the range between about 0.20 to 1.0 equivalent. The compounds of formula 4 where R3represents a C1-C4alkyl, are preferred for this reaction.

Scheme 2

Typical solvents for this halogenation include halogenated alkanes such as dichloromethane, chloroform, chlorobutane, and the like, aromatic solvents such as benzene, xylene, chlorobenzene, and the like, ethers such as tetrahydrofuran, p-dioxane, simple diethyl ether, and the like, and polar aprotic solvents such as acetonitrile, N,N-dimethylformamide, and the like. Optional, can be added an organic base, such as triethylamine, pyridine, N,N-dimethylaniline, or the like. The addition of a catalyst, such as N,N-dimethylformamide, is also optional. Preferred is a method in which the solvent is a acetonitrile, and osnovannatschatelnom. Typically, when acetonitrile is used as solvent, requires no Foundation, no catalyst. The preferred method is carried out by mixing the compounds of formula 4 with acetonitrile. Then, over time, adds a halogenation reagent, and then, the mixture is maintained at the desired temperature until completion of the reaction. The reaction temperature generally is in the range between 20°C and a boiling point of acetonitrile, and the reaction time generally is less than 2 hours. Then the reaction mass is neutralized with inorganic bases such as sodium bicarbonate, sodium hydroxide, and the like, or organic bases, such as sodium acetate. The desired product, compound of formula I may be isolated using methods known to experts in this field, including crystallization, extraction and distillation.

At stage (2), compound of formula I, where R3represents a C1-C4alkyl, ester may be hydrolyzed to compounds of formula I, where R3represents H, to carboxylic acids. The hydrolysis can kataliziruetsa with acids, metal ions and enzymes. Attributively celebrated as an example of acid, which can be used for catalysis of the hydrolysis (see Advanced Organic Chemistry, Third Ed., Jerry Mach, John Wiley & Sons, Inc. New York, 1985, pp. 334-338, review of methods). Methods of hydrolysis, catalyzed by bases, are not recommended for the hydrolysis of compounds of formula I and can lead to decay. The carboxylic acid may be isolated using methods known to experts in this field, including crystallization, extraction and distillation.

At stage (3), as illustrated in scheme 3, the compound of formula I is treated with an oxidizing agent, optionally in the presence of acid. The compound of formula I, where R3represents a C1-C4alkyl (i.e., the preferred product of stage (1)is preferred, as the source material for the stage (3). The oxidizing agent may be hydrogen peroxide, organic peroxides, potassium persulfate, sodium persulfate, ammonium persulfate, monopersulfate potassium (e.g., Oxone®) or potassium permanganate. To achieve full transformation (conversion), you must use at least one equivalent of the oxidizing agent relative to the compound of formula I, preferably, about one to two equivalents. This oxidation is generally carried out in the presence of a solvent. The solvent may be a simple ether, such as tetrahydrofuran, p-dioxane, and the like, complex organic the IDF, such as ethyl acetate, dimethylcarbonate, and the like, or a polar aprotic organic solvent, such as N,N-dimethylformamide, acetonitrile, and the like. Acids suitable for use on stage oxidation, include inorganic acids such as sulfuric acid, phosphoric acid, and the like, and organic acids such as acetic acid, benzoic acid, and the like. Acid, when used, must be used in a proportion greater than 0.1 equivalent, relative to the compound of formula I. For complete conversion, you can use from one to five equivalents of acid. For compounds of formula I, where X represents CR2preferred oxidizing agent is a peroxide, and the oxidation is preferably carried out in the absence of acid. For compounds of formula I, where X represents N, the preferred oxidizing agent is a potassium persulfate, and the oxidation is preferably carried out in the presence of sulfuric acid. The interaction may be carried out by mixing the compounds of formula I in the desired solvent and acid, if used. Then you can add the oxidizer, with convenient speed. The reaction temperature usually varies at least approximately from 0°C to tempera is URS boiling solvent, with the aim of obtaining reasonable time interaction for completion of the reaction, preferably, less than 8 hours. The desired product, compound of formula II, where R3represents a C1-C4the alkyl may be selected using methods known to experts in this field, including crystallization, extraction and distillation.

Scheme 3

At stage (4), as illustrated in scheme 4, the compound of formula II, where R3represents a C1-C4alkyl, i.e. ester, can be converted to the compound of formula II, where R3represents H, i.e. carboxylic acid. How to convert esters to carboxylic acids well known to specialists in this field. The compounds of formula II (R3represents a C1-C4alkyl) can be converted into compounds of formula II (R3represents H) using numerous methods, including nucleophilic cleavage in anhydrous conditions, or hydrolytic methods, including the use of either acids or bases (see T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991, pp. 224-269, review of methods). For the method of scheme 4, the preferred are methods of hydrolysis with alkaline catalysis. Suitable for use with the Foundation of clucalc hydroxides of alkali metals (such as lithium, sodium or potassium). For example, the ester can be dissolved in a mixture of water and alcohol, such as ethanol. When handling sodium hydroxide or potassium hydroxide, an ester of its shades, obtaining sodium or potassium salt of carboxylic acid. Acidification with a strong acid, such as hydrochloric acid or sulfuric acid, yields the carboxylic acid. Carboxylic acid can be isolated by methods known to experts in this field, including crystallization, extraction and distillation.

Scheme 4

It should be noted that certain compounds of formula I, where R1is a halogen, can be obtained from other compounds of formula I, where R1is another halogen or a sulphonate group such as p-toluensulfonate, bansilalpet and methanesulfonate. For example, the compound of formula I, where R1represents Br, can be obtained by processing with hydrogen bromide, the corresponding compounds of formula I, where R1represents Cl or p-toluensulfonate. The interaction is carried out in an appropriate solvent, such as dibromomethane, dichloromethane or acetonitrile. The interaction may be carried out at atmospheric pressure or near, or at a pressure higher than atmospheric pressure, in pressure vessels. When R1,in the initial compound of formula I, represents a halogen, such as Cl, interaction preferably carried out in such a way that the hydrogen halide generated in the reaction is removed by purging or by other appropriate means. The interaction may be carried out at a temperature between about 0 and 100°C, most convenient, near ambient temperature (e.g., about 10-40°C), and more preferably in the range of about between 20 and 30°C. the Addition of the catalyst on the basis of a Lewis acid (for example, tribromide aluminum, to obtain the compounds of formula I, where R1represents Br) can accelerate the reaction. The product of formula I can be isolated using conventional methods known to experts in this field, including extraction, distillation and crystallization.

The initial compounds of the formula I, where R1is a halogen, can be prepared as already described for scheme 2. The initial compounds of the formula I, where R1represents a sulphonate group, can, likewise, be obtained from corresponding compounds of formula 4 using standard methods such as treatment with sulphonylchloride (for example, p-toluensulfonate) and a base such as tertiary and is in (for example, the triethylamine), in an appropriate solvent such as dichloromethane.

Without further explanation, it is assumed that the person skilled in the art using the preceding description can utilize the present invention in its most full. For this reason, the following examples should be considered only as illustrative and not limiting description in any way. The source material for the following examples may not necessarily be prepared by using a specific method of obtaining the procedure is described in other examples. Percentages represent the percent by weight (mass), except mixtures of chromatographic solvents or those places where specified otherwise. Share and interest for mixtures of chromatographic solvents specified by volume, unless otherwise stated. Spectra1H NMR indicated in ppm, in weak fields, from tetramethylsilane; "s" means singlet, "d" means doublet, "t" means triplet, "q" means Quartet, "m" means multiplet, "dd" means doublet of doublets, "dt" means doublet of triplets, and "br s" means broadened singlet.

EXAMPLE 1

Obtain ethyl 5-oxo-2-phenyl-3-pyrazolecarboxylate (alternative title ethyl 1-phenyl-3-pyrazolidine-5-carboxylate) using diethylmaleate

B300-ml chetyrehosnuju flask, equipped with a mechanical stirrer, thermometer, dropping funnel for adding reagent, reflux condenser and input for nitrogen load 80 ml of absolute ethanol, 80,0 ml (0,214 mol) 21% ethoxide sodium in ethanol and 20.0 ml (0,203 mol) of phenylhydrazine. The orange solution is treated dropwise 40,0 ml (0,247 mol) diethylmaleate for about 18 minutes. The temperature of the reaction mass increases from 25 to 38°C within the first 5 minutes add. Use a water bath alternately with the continuation added to maintain the reaction temperature between 38-42°C. the Obtained orange-red solution stand at ambient conditions for 30 minutes. It is then transferred into a separating funnel containing 20,0 ml (0,349 mol) of glacial acetic acid and 700 ml of water. The mixture is extracted with 250 ml dichloromethane. The extract is dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. Received black-and-yellow oil (52.7 g) is diluted with 100 ml of a simple ester, with crystallization of the product is fast enough to cause a slight boil. The suspension was incubated for 2 hours at ambient conditions. Then it is cooled to approximately 0°C. the Product is separated by filtration, washed with 2 x 20 ml simple cold ether, and then air-dried on the filter in those which begins approximately 15 minutes. The product consists of 29.1 g (61%) of a white powder with high crystallinity. For1H NMR no significant impurities not detected. The filtrate is concentrated to 20.8 g of brown oil. Oil analysis shows the presence of an additional 6.4 g (13%) of the desired product. Therefore, the overall yield of the reaction is 74%.

1H NMR (DMSO-d6) δ of 10.25 (s, 1H), 7,32 (m, 2H), 7,15 (d, 2H), 7,00 (t, 1H), br4.61 (DD, 1H), is 4.21 (q, 2H), 2,95 (DD, 1H), 2,45 (DD, 1H), 1,25 (t, 3H).

EXAMPLE 2

Obtain ethyl 5-oxo-2-phenyl-3-pyrazolecarboxylate (alternative title ethyl 1-phenyl-3-pyrazolidine-5-carboxylate) using diethylfumarate

In a 500-ml chetyrehosnuju flask, equipped with a mechanical stirrer, thermometer, dropping funnel for adding reagent, reflux condenser and input for nitrogen, charged 150 ml of absolute ethanol, 15.0 g (0,212 mol) of 96% ethoxide sodium in ethanol and 20.0 ml (0,203 mol) of phenylhydrazine. The orange mixture is treated dropwise 40,0 ml (0,247 mol) of diethylfumarate over a period of 75 minutes. During the addition the temperature of the reaction mass increases from 28 to 37°C, the maximum, and the final temperature is 32°C. Received several turbid orange solution can withstand the environmental conditions within 135 minutes. Then the reaction mixture was poured into a separating funnel containing 15.0 ml (0,262 supposedly is) glacial acetic acid and 700 ml of water. The mixture is extracted with 150 ml of dichloromethane. The extract is dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The obtained brownish-yellow oil (41,3 g) is diluted with 100 ml of a simple ester. Add a few seed crystals. The mixture was incubated for 30 minutes at ambient conditions. Then it is cooled to approximately 0°C. the Product is separated by filtration, washed with 2 x 10 ml simple cold ether, and then air-dried on the filter for about 15 minutes. The product consists of 9.5 g (20%) of a white powder with high crystallinity. For1H NMR no significant impurities not detected. The filtrate is concentrated to 31 g of brown oil. Oil analysis shows the presence of additional 7,8 g (16%) of the desired product. Therefore, the overall selectivity of the reaction is 36%.

EXAMPLE 3

Obtain ethyl 5-oxo-2-(2-pyridinyl)-3-pyrazolecarboxylate (alternative title ethyl 1-(2-pyridinyl)-3-pyrazolidine-5-carboxylate)

200-ml chetyrehosnuju flask, equipped with a mechanical stirrer, thermometer, dropping funnel for adding reagent, reflux condenser and input for nitrogen load 18 ml of absolute ethanol and 18.0 ml (0,0482 mol) 21% ethoxide sodium in ethanol and of 5.00 g (0,0458 mol) of 2-hydrazinopyridazine. The solution is heated to 34°C. Then it clicks the functioning dropwise to 9.0 ml (0,056 mol) diethylmaleate within a period of 20 minutes. During the addition the temperature of the reaction mass increases up to 48°C. the Obtained orange solution stand at ambient conditions for up to 85 minutes. Then it was poured into a separating funnel containing 4.0 ml (0,070 mol) of glacial acetic acid and 300 ml of water. The mixture is extracted with 2 x 50 ml dichloromethane. The extract is dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The obtained orange oil (10.7 g) is subjected to flash chromatography on a column of 200 g of silica gel using 4% methanol in chloroform as eluent (50 ml fractions). Fractions 9-12 is evaporated on a rotary evaporator to obtain 3.00 g of orange oil, which contains 77% of the desired product, 15% of chloroform and 8% diethyl 2-ethoxymethylene. Fractions 13-17 concentrate with the receipt of 4.75 g of an orange-yellow oil, which contains 94% of the desired product and 6% of chloroform. Fractions 18-21 concentrate to obtain 1.51 g of olive-green oil, which contains 80% of the desired product and 20% of chloroform. The overall yield of the desired product is 8.0 g (74%).

1H NMR (DMSO-d6) δ for 10.68 (ush,, 1H), they were 8.22 (d, 1H), of 7.70 (t, 1H), 6.90 to (m, 2H), 5,33 (DD, 1H), 4,17 (kV, 2H), 3,05 (DD, 1H), 2,48 (DD, 1H), 1,21 (t, 3H).

EXAMPLE 4

Obtain ethyl 2-(2-chlorophenyl)-5-oxo-3-pyrazolecarboxylate (alternative title ethyl 1-(2-chlorophenyl)-3-pyrazolidine-5-carboxylate)

p> In a 250 ml chetyrehosnuju flask, equipped with a mechanical stirrer, thermometer, dropping funnel for adding reagent, reflux condenser and input for nitrogen load 40 ml of absolute ethanol, 40,0 ml (0,107 mol) 21% ethoxide sodium in ethanol and 14.5 g (is 0.102 mol) of (2-chlorophenyl)hydrazine. The purple solution was heated to 35°C. Then treated dropwise 19,0 ml (0,117 mol) of diethylmaleate over a period of about 23 minutes. A water/ice bath is used interchangeably with the continuation added to maintain the reaction temperature between 35-40°C. the Reaction mixture was kept at this temperature for 30 minutes. Then it is added into a separating funnel containing 10.0 ml (0,175 mol) of glacial acetic acid and 400 ml of water. The mixture is extracted with 2 x 100 ml of dichloromethane. The extract is dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The obtained dark brown oil (31.0 g) crystallized upon standing. The material is suspended in 100 ml of simple ether and the suspension is stirred for about 1 hour. The product is separated by filtration, washed with 50 ml of simple ether, and then dried over night at room temperature in vacuum. The product consists of 12.5 g (46%) of crystalline powder. For1H NMR no significant impurities not detected. The filtrate is concentrated is to 16.3 g of brown oil. Oil analysis shows the presence of additional 6.7 g (25%) of the desired product. Therefore, the overall selectivity of the reaction is 71%.

1H NMR (DMSO-d6) δ 10,14 (s, 1H), 7,47 (6, 1H), 7,32 (m, 2H), 7,14 (t, 1H), 4,39 (d, 1H), 4,19 (kV, 2H), of 3.07 (DD, 1H), 2,29 (d, 1H), 1,22 (t, 3H).

EXAMPLE 5

Obtain ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolecarboxylate (alternative title ethyl 1-(3-chloro-2-pyridinyl)-3-pyrazolidine-5-carboxylate).

2-l chetyrehosnuju flask, equipped with a mechanical stirrer, thermometer, dropping funnel for adding reagent, reflux condenser and input for nitrogen load 250 ml of absolute ethanol and 190 ml (0,504 mol) 21% ethoxide sodium in ethanol. The mixture is heated under reflux at about 83°C. Then treated to 68.0 g (0,474 mol) 3-chloro-2(1H)-pyridinone hydrazone (alternative name 3-chloro-2-hydrazinopyridazine). The mixture is again heated under reflux over a period of 5 minutes. Then the yellow suspension is treated dropwise 88,0 ml (0,544 mol) of diethylmaleate over a period of 5 minutes. While adding the rate of boil-off is considerably increased. To finish adding all the source material is dissolved. The obtained orange-red solution is incubated under reflux for 10 minutes. After cooling to 65°C, the reaction mixture is treated 50,0 m is (0,873 mol) of glacial acetic acid. A precipitate. The mixture is diluted with 650 ml of water, while the precipitate dissolves. The orange solution is cooled in an ice bath. The product begins to precipitate at 28°C. the Suspension is incubated at about 2°C for 2 hours. The product is separated by filtration, washed with 3 x 50 ml of 40% aqueous solution of ethanol, and then air-dried on the filter for about 1 hour. The product consists of 70,3 g (55%) of a light orange powder with a high degree of crystallinity. For1H NMR no significant impurities not detected.

1H NMR (DMSO-d6) δ 10,18 (s, 1H), 8,27 (d, 1H), 7,92 (d, 1H), 7,20 (DD, 1H), 4,84 (d, 1H), 4,20 (kV, 2H), 2.91 in (DD, 1H), 2,35 (d, 1H), 1,22 (t, 3H).

EXAMPLE 6

Obtain ethyl 3-chloro-4,5-dihydro-1-phenyl-1H-pyrazole-5-carboxylate (alternatively named ethyl 1-phenyl-3-chloro-2-pyrazolin-5-carboxylate)

EXAMPLE 6A

The use of phosphorus oxychloride in acetonitrile, in the absence of grounds

In a 500-ml chetyrehosnuju flask, equipped with a mechanical stirrer, thermometer, dropping funnel for adding reagent, reflux condenser and input for nitrogen, charged 150 ml of acetonitrile, 25,0 g (0,107 mol) of ethyl 5-oxo-2-phenyl-3-pyrazolecarboxylate and 11.0 ml (amount of 0.118 mol) of phosphorus oxychloride. Light yellow solution is heated to 78-80°C, within a period of 45 minutes. After cooling to 54°C received a blue-green mixture on srabatyvayut dropwise with a solution of 25.0 g (0,298 mol) of sodium bicarbonate in 250 ml of water. During the 15-minute add separate orange oil. After stirring for about 5 minutes the pH of the mixture is approximately 1. Additional 10.0 g (0,119 mol) of sodium bicarbonate is added in the form of a solid product for a period of approximately 3 minutes, which leads to a final pH of approximately 6. The mixture is diluted with 400 ml of water, while orange oil crystallizes. The crystal mass is crushed with a spatula. The product is separated by filtration, washed with 4 x 100 ml of water, and then air-dried on the filter for about 2 hours. The product consists of 24.5 g (91%) friable crystalline light yellow powder. For1H NMR no significant impurities not detected.

1H NMR (DMSO-d6) δ to 2.74 (t, 2H), to 6.88 (d, 2H), 6,83 (t, 1H), 5,02 (DD, 1H), 4,14 (kV, 2H), 3,68 (DD, 1H), 3,34 (d, 1H), of 1.16 (t, 3H).

EXAMPLE 6B

The use of phosphorus oxychloride in chloroform in the absence of grounds

In a 100-ml two-neck flask, equipped with magnetic stirrer, thermometer, reflux condenser and input for nitrogen load 50 ml of chloroform, 5,00 g (0,0213 mol) of ethyl 5-oxo-2-phenyl-3-pyrazolecarboxylate, 2.10 ml (0,0225 mol) of phosphorus oxychloride and 2 drops of N,N-dimethylformamide. Red-orange solution is heated under reflux for 64°C for a period of 60 minutes. The resulting mixture, yellow-brown LM the bone and dark green resinous solid product maintained at the boil under reflux for 140 minutes. Then diluted with 100 ml of dichloromethane and transferred into a separating funnel. The solution is washed with twice 50 ml of 6% aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate, filtered, then concentrated on a rotary evaporator. The crude product consists of 1.50 g of orange oil, which crystallized upon standing. Analysis of the crude product by using1H NMR shows that it is approximately 65% of the desired product and 35% of the source material. The yield of the desired product, therefore, is approximately 18%.

EXAMPLE 6C

The use of phosphorus oxychloride in chloroform in the presence of triethylamine

In a 100-ml dvuhgolosy flask, equipped with magnetic stirrer, thermometer, reflux condenser and input for nitrogen load 20 ml of chloroform, 2.00 g (0,00854 mol) of ethyl 5-oxo-2-phenyl-3-pyrazolecarboxylate, 1,30 ml (0,00933 mol) of triethylamine, 2 drops of N,N-dimethylformamide and 0,0850 ml (0,00912 mol) of phosphorus oxychloride. When added phosphorus oxychloride, is immediate and violent reaction. The mixture is heated under reflux for 64°C, for 25 minutes. The obtained yellow solution was diluted with 50 ml of water, and then treated with 3.0 g (being 0.036 mol) of solid sodium bicarbonate. A two-phase mixture is stirred for 50 minutes under conditions of OK is usausa environment. Then transferred into a separating funnel and diluted with 100 ml dichloromethane. The organic layer is separated and then washed in turn with 50 ml of 5.5% aqueous solution of hydrochloric acid and 50 ml of 3.8% aqueous solution of sodium carbonate. The washed organic layer is dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The crude product consists of 1.90 g of a yellow oil which crystallizes upon standing. Analysis of the crude product by using1H NMR shows that it is approximately 94% of the desired product, 2% starting material and 2% unspecified impurities. The yield of the desired product, therefore, is approximately 83%.

EXAMPLE 7

Obtain ethyl 3-chloro-4,5-dihydro-1-(2-pyridinyl)-1H-pyrazole-5-carboxylate (alternatively named ethyl 1-(2-pyridinyl)-3-chloro-2-pyrazolin-5-carboxylate)

In a 250 ml chetyrehosnuju flask, equipped with a mechanical stirrer, thermometer, reflux condenser and input for nitrogen load 50 ml of acetonitrile, 4,70 g (0,0188 mol) of 5-oxo-2-(2-pyridinyl)-3-pyrazolecarboxylate and 2.00 ml (0,0215 mol) of phosphorus oxychloride. The mixture is heated itself from 22 to 33°C. After incubation for 60 minutes at ambient conditions a sample is taken. Analysis using the1H NMR shows a 70% conversion of starting material to desired product. The mixture is heated on atnam refrigerator at 85° C for 80 minutes. Heating the casing removed. The yellow-orange solution was diluted with 50 ml of water. Then treated dropwise to 3.9 g (0,049 mol) of 50% aqueous solution of caustic soda, to obtain a pH of about 7.5. After stirring for 20 minutes the pH of the mixture drops to about 3. Add an additional 3.0 g (of 0.038 mol) of 50% aqueous solution of caustic soda, while pH increases approximately to 9.0. To bring the pH to approximately 7.5 to add a small amount of concentrated hydrochloric acid. The neutralized mixture is transferred into a separating funnel containing 300 ml of water and 100 ml dichloromethane. The organic layer is separated, dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The product consists of 4.10 g (84%) of pale yellow oil, which crystallizes upon standing. The only appreciable impurities detected using1H NMR represent 1.0% of the initial material and 0.6% of acetonitrile.

1H NMR (DMSO-d6) δ 8,18 (d, 1H), 8,63 (t, 1H), 8,13 (d, 1H), 7,80 (t, 1H), 5,08 (DD, 1H), 4,11 (m, 2H), 3,65 (DD, 1H), 3.27 to (DD, 1H), 1.14 in (t, 3H).

EXAMPLE 8

Obtain ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (alternatively named ethyl 1-(3-chloro-2-pyridinyl)-3-chloro-2-pyrazolin-5-carboxylate)

2-l chetyrehosnuju flask, equipped with a mechanical stirrer, a thermometer is m, reflux and input for nitrogen load 1000 ml of acetonitrile, 91,0 g (of 0.337 mol) of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolecarboxylate and of 35.0 ml (0,375 mol) of phosphorus oxychloride. Adding phosphorus oxychloride, the mixture is heated itself from 22 to 25°C and a precipitate. Light yellow suspension is heated under reflux at 83°C for a period of 35 minutes while the precipitate dissolves. The obtained orange solution was kept at the boil under reflux for 45 minutes, while it becomes black and green. The reflux condenser is replaced by a nozzle for distillation and remove 650 ml of solvent by distillation. The second 2-liter chetyrehosnuju flask, equipped with a mechanical stirrer, load 130 g (1.55 mol) of sodium bicarbonate and 400 ml of water. A concentrated reaction mixture was added to a suspension of sodium bicarbonate over a period of 15 minutes. The obtained two-phase mixture was vigorously stirred for 20 minutes, during this time the evolution of gas ceases. The mixture is diluted with 250 ml of dichloromethane and then stirred for 50 minutes. The mixture is treated with 11 g of diatomaceous earth Celite 545®and then filtered to remove a black resinous substance, which prevents the separation of the phases. Since the filtrate is slowly divided into different phases, it is diluted with 200 ml of dihormati the a and 200 ml of water and treated with an additional 15 g of Celite 545® . The mixture is filtered and the filtrate is transferred into a separating funnel. The heavier dark green organic layer is separated. 50 ml of a coarse-grained layer, re-filtered, and then added to the organic layer. The organic solution (800 ml) is treated with 30 g of magnesium sulfate and 12 g of silica gel and the suspension is stirred with a magnetic stirrer for 30 minutes. The suspension was filtered to remove the magnesium sulfate and silica gel, in this case it becomes blue-green. The filter cake was washed with 100 ml dichloromethane. The filtrate is concentrated on a rotary evaporator. The product consists of 92.0 g (93%) of a dark amber oil. The only appreciable impurities detected using1H NMR, represent 1% of the source material and 0.7% acetonitrile.

1H NMR (DMSO-d6) δ to 8.12 (d, 1H), to 7.84 (d, 1H), 7,00 (DD, 1H), 5.25-inch (DD, 1H), 4,11 (kV, 2H), to 3.58 (DD, 1H), 3,26 (DD, 1H)and 1.15 (t, 3H).

EXAMPLE 9

Obtain ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (alternatively named ethyl 1-(3-chloro-2-pyridinyl)-3-bromo-2-pyrazolin-5-carboxylate)

EXAMPLE 9A

Using oxybromide phosphorus

1-l chetyrehosnuju flask, equipped with a mechanical stirrer, thermometer, reflux condenser and the input of the nitrogen load of 400 ml of acetonitrile, 50.0 g (0.185 mol) of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolecarboxylate and 34,0 g (0,119 mol) is dibromide phosphorus. The orange suspension is heated under reflux at 83°C for a period of 20 minutes. The obtained turbid orange solution was kept at the boil under reflux for 75 minutes, during this time, a dense yellow-brown crystalline residue. The reflux condenser is replaced by a nozzle for distillation and collect 300 ml opaque colorless distillate. The second 1-l chetyrehosnuju flask, equipped with a mechanical stirrer, a load of 45 g (0.54 mol) of sodium bicarbonate and 200 ml of water. A concentrated reaction mixture was added to a suspension of sodium bicarbonate over a period of 5 minutes. The obtained two-phase mixture was vigorously stirred for 5 minutes, during this time the evolution of gas ceases. The mixture is diluted with 200 ml of dichloromethane and then stirred for 75 minutes. The mixture is treated with 5 g Celite 545®and then filtered to remove a brown resinous substance. The filtrate is transferred into a separating funnel. Brown organic layer (400 ml) is separated and then treated with 15 g of magnesium sulfate and 2.0 g of activated carbon Darco G60. The resulting suspension is stirred with a magnetic stirrer for 15 minutes and then filtered to remove the magnesium sulfate and charcoal. The green filtrate is treated with 3 g of silica gel and is infilled within a few minutes. Blue-green silica gel UD is collected by filtration and the filtrate concentrated on a rotary evaporator. The product consists of 58.6 g (95%) of a light amber oil which crystallized upon standing. The only appreciable impurity observed using1H NMR represents a 0.3% acetonitrile.

1H NMR (DMSO-d6) δ to 8.12 (d, 1H), to 7.84 (d, 1H), 6,99 (DD, 1H), 5,20 (DD, 1H), 4,11 (kV, 2H), 3,60 (DD, 1H), 3,29 (DD, 1H)and 1.15 (t, 3H).

EXAMPLE 9B

Using pentabromide phosphorus

1-l chetyrehosnuju flask, equipped with a mechanical stirrer, thermometer, reflux condenser and input for nitrogen load 330 ml of acetonitrile, 52.0 g (0.193 mol) of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolecarboxylate and of 41.0 g (0.0952 mol) of pentabromide phosphorus. The orange suspension is heated under reflux at 84°C for a period of 20 minutes. Received a brick-red mixture was kept at boiling under reflux for 90 minutes, during this time, a dense yellow-brown crystalline residue. The reflux condenser is replaced by a nozzle for distillation and collect 220 ml opaque colorless distillate. The second 1-l chetyrehosnuju flask, equipped with a mechanical stirrer, a load of 40 g (0.48 mol) of sodium bicarbonate and 200 ml of water. A concentrated reaction mixture was added to a suspension of sodium bicarbonate over a period of 5 minutes. The obtained two-phase mixture was vigorously stirred for 10 minutes, during this time, you shall bookmark gas stops. The mixture is diluted with 200 ml of dichloromethane and then stirred for 10 minutes. The mixture is treated with 5 g Celite 545®and then filtered to remove purple resinous substance. The filter cake was washed with 50 ml of dichloromethane. The filtrate is transferred into a separating funnel. Purple-red organic layer (400 ml) is separated, then treated with 15 g of magnesium sulfate and 2.2 g of activated carbon Darco G60. The suspension is stirred with a magnetic stirrer for 40 minutes. The suspension was filtered to remove the magnesium sulfate and charcoal. The filtrate is concentrated on a rotary evaporator. The product consists of 61.2 g (95%) of a dark amber oil which crystallized upon standing. The only appreciable impurity observed using1H NMR represents 0.7% of acetonitrile.

1H NMR (DMSO-d6) δ to 8.12 (d, 1H), to 7.84 (d, 1H), 6,99 (DD, 1H), 5,20 (DD, 1H), 4,11 (kV, 2H), 3,60 (DD, 1H), 3,29 (DD, 1H)and 1.15 (t, 3H).

EXAMPLE 10

Obtain ethyl 3-chloro-1-phenyl-1H-pyrazole-5-carboxylate (alternatively named ethyl 1-phenyl-3-chloropyrazole-5-carboxylate)

EXAMPLE 10A

The use of hydrogen peroxide

In a 100-ml dvuhgolosy flask, equipped with magnetic stirrer, thermometer, reflux condenser and the input of the nitrogen load of 1.50 g (0,00594 mol) ethyl 3-chloro-4,5-dihydro-1-phenyl-1H-pyrazole-5-carboxylate and 15 ml of acetonitrile. The mixture is heated to 80°C. Then her amrabat who live 0,700 ml (0,00685 mol) of 30% aqueous hydrogen peroxide solution. The mixture is maintained at 78-80°C for 5 hours. Then the reaction mass is added to 70 ml of water. Usageprice the product is separated by filtration, and then washed with 15 ml of water. The wet cake of the precipitate is dissolved in 100 ml of dichloromethane. The solution is dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The product consists of 1.24 g (approximately 79%) of an orange oil, which crystallized upon standing. As shown1H NMR, the resulting material contains approximately 95% pure product.

1H NMR (DMSO-d6) δ to 7.50 (s, 5H), 7,20 (s, 1H), 7,92 (d, 1H), 4,18 (kV, 2H), 1.14 in (t, 3H).

EXAMPLE 10B

The use of manganese dioxide

In a 100-ml dvuhgolosy flask, equipped with magnetic stirrer, thermometer, reflux condenser and the input of the nitrogen load of 3.00 g (0,0119 mol) ethyl 3-chloro-4,5-dihydro-1-phenyl-1H-pyrazole-5-carboxylate, 25 ml of chloroform and 2.50 g (0,0245 mol) of activated manganese dioxide. The mixture is heated at boiling under reflux at 62°C for a period of 1 hour. Analysis of a sample of the reaction mixture with1H NMR shows about 6% conversion of the raw material, mostly in the desired ethyl 1-phenyl-3-chloropyrazole-5-carboxylate. The mixture was kept at boiling under reflux for an additional 5 hours. The analysis of the second sample shows approximately 9% of the Tran is irreducible.

EXAMPLE 10C

The use of sodium hypochlorite

In a 100-ml dvuhgolosy flask, equipped with magnetic stirrer, thermometer, reflux condenser and the input of the nitrogen load of 1.00 g (0,00396 mol) ethyl 3-chloro-4,5-dihydro-1-phenyl-1H-pyrazole-5-carboxylate, 10 ml of acetonitrile, 0.55 g (0,0040 mol) of sodium dihydrophosphate monohydrate and the 5.65 g (0,00398 mol) of 5.25% aqueous sodium hypochlorite solution. The orange solution is kept in the environment for up to 85 minutes. Analysis of a sample of the reaction mass using1H NMR shows approximately 71% conversion of starting material in two main product. The solution is heated to 60°C for 60 minutes. The analysis of the second sample shows no growth transformation relative to the first sample. The reaction mixture was treated with additional 3.00 g (0,00211 mol) of 5.25% aqueous sodium hypochlorite solution. After incubation for 60 minutes at 60°C, the reaction mass is added to 100 ml of water. The mixture is extracted with 100 ml dichloromethane. The extract is separated, dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The crude product consists of 0.92 g of red-orange oil.1H NMR shows that the crude product consists mainly of ethyl 3-chloro-1-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (alternatively named ethyl 1-(4-chlorophenyl)-3-chloro-2-piraso the ine-5-carboxylate and ethyl 3-chloro-1-(2-chlorophenyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (alternatively named ethyl 1-(2-chlorophenyl)-3-chloro-2-pyrazolin-5-carboxylate), in the ratio 2:1. The isomer can be separated by chromatography on silica gel using 10% ethyl acetate in hexane as eluent.1H NMR for ethyl 3-chloro-1-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (DMSO-d6) δ 7,28 (d, 2H), 6.89 in (d, 2H), 5,08 (DD, 1H), 4,14 (kV, 2H), 3,71 (DD, 1H), 3,37 (DD, 1H), of 1.16 (t, 3H).1H NMR for ethyl 3-chloro-1-(2-chlorophenyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (DMSO-d6) δ 7,41 (d, 1H), 7,30 (m, 2H), 7,14 (m, 1H), 5,22 (DD, 1H), 3,90 (kV, 2H), 3,68 (DD, 1H), 3,38 (DD, 1H), of 0.91 (t, 3H).

EXAMPLE 11

Obtain ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (alternatively named ethyl 1-(3-chloro-2-pyridinyl)-3-chloropyrazole-5-carboxylate)

2-l chetyrehosnuju flask, equipped with a mechanical stirrer, thermometer, reflux condenser and the input of the nitrogen load of 99.5 g (0,328 mol) ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate, 1000 ml of acetonitrile with a purity of 95% to 35.0 ml (0,661 mol) of 98% sulfuric acid. The mixture is heated itself from 22 to 35°C adding sulfuric acid. After stirring for several minutes, the mixture is treated with 140 g (0,518 mol) of potassium persulfate. The suspension is heated under reflux at 84°C for 4.5 hours. The obtained orange suspension is filtered in a while it is still warm (50-65° (C)to remove the fine white precipitate. The precipitate on the filter PR is myauth 50 ml of acetonitrile. The filtrate is concentrated on a rotary evaporator to approximately 500 ml of the second 2-l chetyrehosnuju flask, equipped with a mechanical stirrer, load 1250 ml of water. To water add a concentrated reaction mass over a period of about 5 minutes. The product is separated by filtration, washed with 3 x 125 ml 25% aqueous solution of acetonitrile, washed once with 100 ml of water, and then dried overnight in vacuum at room temperature. The product consists of 79,3 g (82%) of orange crystalline powder. The only appreciable impurities detected using1H NMR, represent approximately 1.9% water and 0.6% of acetonitrile.

1H NMR (DMSO-d6) δ 8,59 (d, 1H), scored 8.38 (d, 1H), 7,71 (DD, 1H), 7,31 (s, 1H), 4.16 the (q, 2H), of 1.09 (t, 3H).

EXAMPLE 12

Obtain ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (alternatively named ethyl 1-(3-chloro-2-pyridinyl)-3-bromopyrazole-5-carboxylate)

1-l chetyrehosnuju flask, equipped with a mechanical stirrer, thermometer, reflux condenser and input for nitrogen, download with 40.2 g (0,121 mol) ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate, 300 ml of acetonitrile and 13.0 ml (0,245 mol) of 98% sulfuric acid. The mixture is heated itself from 22 to 36°C, adding sulfuric acid. After stirring for several minutes, the mixture is treated 48,0 g (0,178 mol) of Peralta is and potassium. The suspension is heated at the boil under reflux at 84°C for 2 hours. The obtained orange suspension is filtered in a while it is still warm (50-65° (C)to remove the white precipitate. The filter cake was washed with 2 x 50 ml of acetonitrile. The filtrate is concentrated on a rotary evaporator to approximately 200 ml of the second 1-l chetyrehosnuju flask, equipped with a mechanical stirrer, download 400 ml of water. To water add a concentrated reaction mass over a period of about 5 minutes. The product is separated by filtration, washed with 100 ml of 20% aqueous solution of acetonitrile, washed with 75 ml of water, and then air-dried on the filter for 1 hour. The product consists of 36.6 g (90%) of orange crystalline powder. The only appreciable impurities detected using1H NMR, represent approximately 1% of the unknown product and 0.5% acetonitrile.

1H NMR (DMSO-d6) δ 8,59 (d, 1H), 8,39 (d, 1H), 7,72 (DD, 1H), 7,35 (s, 1H), 4.16 the (q, 2H), of 1.09 (t,3H).

EXAMPLE 13

Obtain 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (alternative name 1-(3-chloro-2-pyridinyl)-3-chloropyrazole-5-carboxylic acid)

1-l chetyrehosnuju flask, equipped with a mechanical stirrer, thermometer and input for nitrogen load to 79.3 g (0,270 mol) 97.5% of ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate, 260 ml of methanol is, 140 ml of water and 13.0 g (0,325 mol) of pellets of sodium hydroxide. The mixture is heated itself from 22 to 35°C, and the source material begins to dissolve when adding sodium hydroxide. After stirring for 45 minutes at ambient conditions entire source material is dissolved. The obtained orange-brown solution was concentrated on a rotary evaporator to about 250 ml. and Then concentrated reaction mixture is diluted with 400 ml of water. The aqueous solution is extracted with 200 ml of a simple ester. The aqueous layer was transferred into a 1-l Erlenmeyer flask equipped with a magnetic stirrer. Then the solution is treated dropwise to 36.0 g (0,355 mol) of concentrated hydrochloric acid over a period of about 10 minutes. The product is separated by filtration, re-suspended 2 x 200 ml of water, the upper layer is washed once with 100 ml of water, and then air-dried on the filter for 1.5 hours. The product consists of to 58.1 g (83%) of crystalline light brown powder. Approximately 0.7% of the common ether is the only appreciable impurity detected using1H NMR.

1H NMR (DMSO-d6) δ 13,95 (USS, 1H), 8,56 (d, 1H), of 8.25 (d, 1H), 7,68 (DD, 1H), 7,20 (s, 1H).

EXAMPLE 14

Obtain 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (alternative name 1-(3-chloro-2-pyridinyl)-3-bromopyrazole-5-carboxylic who Isleta)

In a 300-ml chetyrehosnuju flask, equipped with a mechanical stirrer, thermometer and input for nitrogen load of 25.0 g (0,0756 mol) ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate with a purity of 98.5%, 75 ml of methanol, 50 ml of water and 3.30 g (0,0825 mol) of pellets of sodium hydroxide. The mixture is heated itself from 29 to 34°C, and the source material begins to dissolve when adding sodium hydroxide. After stirring for 90 minutes at ambient conditions entire source material is dissolved. The obtained dark orange solution was concentrated to approximately 90 ml on a rotary evaporator. Then the concentrated reaction mixture is diluted with 160 ml of water. The aqueous solution is extracted with 100 ml of a simple ester. The aqueous layer was transferred into a 500-ml Erlenmeyer flask with a magnetic stir bar. Then the solution is treated dropwise of 8.50 g (0,0839 mol) of concentrated hydrochloric acid over a period of about 10 minutes. The product is separated by filtration, re-suspended 2 x 40 ml of water, the upper layer is washed once with 25 ml water, and then air-dried on the filter for 2 hours. The product consists of 20.9 g (91%) of crystalline yellow-brown powder. The only appreciable impurities detected using1H NMR, represent about 0.8% of the unknown product and 0.7% simple ether.1N I Is R (DMSO-d 6) δ 13,95 (USS, 1H), 8,56 (d, 1H), of 8.25 (d, 1H), 7,68 (DD, 1H), 7,25 (s, 1H).

EXAMPLE 15

Obtain ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro - 1H-pyrazole-5-carboxylate from ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate using HBR

Bromide, hydrogen is bubbled through a solution of ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (8,45 g of 29.3 mmol) in dibromomethane (85 ml). After 90 minutes, the gas flow is stopped and the reaction mixture is washed with aqueous sodium bicarbonate solution (100 ml). The organic phase is dried and evaporated under reduced pressure to obtain specified in the header of the product as oil (9.7 g, yield 99%), which crystallized upon standing.

1H NMR (CDC13) δ 8,07 (DD, J =1,6, 4,8gts, 1H), 7,65 (DD, J =1,6, 7,8gts, 1H), 6,85 (DD, J =4,7, 7,Hz, 1H), 5.25 in (X of ABX, 1H, J =9,3, 11,GC), 4,18 (kV, 2H), 3,44 (1/2 of AB in a series of ABX, J =11,7, 17,3 Hz, 1H), 3,24 (1/2 of AB in ABX series, J =9,3, 17,3 Hz, 1H), 1,19 (t, 3H).

The following example 16 illustrates obtain ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-were-sulfonyl]oxy]-1H-pyrazole-5-carboxylate, which can be used to obtain ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate, using techniques similar to those described in example 15.

EXAMPLE 16

Obtain ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[4-were)sulfonyl]oxy]-1H-pyrazole-5-carboxyla is and

The triethylamine (3.75 g, 37,1 mmol) is added dropwise to a mixture of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolecarboxylate (10.0 g, 37,1 mmol) and p-toluensulfonyl chloride (7,07 g, 37,1 mmol) in dichloromethane (100 ml)at 0°C. Add a further portion of p-toluensulfonyl chloride (0.35 g, to 1.83 mmol) and triethylamine (0,19 g, 1.88 mmol). Then reaction mixture was allow to warm to room temperature and stirred her during the night. The mixture is then diluted with dichloromethane (200 ml) and washed with water (3 x 70 ml). The organic phase is dried and evaporated to obtain specified in the header of the product as oil (13,7 g, yield 87%), which slowly forms crystals. The product, recrystallized from ethyl acetate/hexane, melts at 99,5-100°C.

IR (nujol): 1740, 1638, 1576, 1446, 1343, 1296, 1228, 1191, 1178, 1084, 1027,948, 969, 868, 845 cm-1.

1H NMR (CDC13) δ 8,01 (DD, J =1,4, 4,Hz, 1H), 7,95 (d, J =8,4 Hz, 2H), 7,56 (DD, J =1,6, 7,8gts, 1H), was 7.36 (d, J =8,4 Hz, 2H), 6,79 (DD, J =4,6, 7,Hz, 1H), 5,72 (X of ABX, J =9, 11,8gts, 1H), 4.16 the (q, 2H), 3,33 (1/2 of AB in a series of ABX, J =17,5, and 11.8 Hz, 1H), 3,12 (1/2 of AB in a series of ABX, J =17,3, Hz, 1H), of 2.45 (s, 3H), 1,19 (t, 3H).

Using the procedures described herein together with methods known in this field, can be obtained the following compounds of tables 1-3. The tables use the following abbreviations: t represents a tertiary, s is a secondary, n is a normal the tion, i is the best, Me represents methyl, Et represents ethyl, Pr represents propyl, i-Pr represents isopropyl and t-Bu represents a tertiary butyl.

Table 1

R1represents Cl
X represents NX represents CHX represents CClX represents CBr
R2R3R2R3R2R3R2R3R2R3R2R3R2R3R2R3
ClHBrHClHBrHClHBrHClHBrH
ClMeBrMeClMeBrMeCle BrMeClMeBrMe
ClEtBrEtClEtBrEtClEtBrEtClEtBrEt
Cln-PrBrn-PrCln-PrBrn-PrCln-PrBrn-PrCln-PrBrn-Pr
Cli-PrBri-PrCli-PrBri-PrCli-PrBri-PrCli-PrBri-Pr
Cln-BuBrn-BuCln-BuBrn-BuCln-BuBrn-BuCln-BuBrn-Bu
Cli-BuBri-BuCli-BuBri-BuCli-BuBr Cli-BuBri-Bu
Cls-BuBrs-BuCls-BuBrs-BuCls-BuBrs-BuCls-BuBrs-Bu
Clt-BuBrt-BuClt-BuBrt-BuClt-BuBrt-BuClt-BuBrt-Bu

R1is a Br
X represents NX represents CHX represents CClX represents CBr
R2R3R2R3R2R3R2R3R2R3R2R3R2R3R2R3
ClH BrHClHBrHClHBrHClHBrH
ClMeBrMeClMeBrMeClMeBrMeClMeBrMe
ClEtBrEtClEtBrEtClEtBrEtClEtBrEt
Cln-PrBrn-PrCln-PrBrn-PrCln-PrBrn-PrCln-PrBrn-Pr
Cli-PrBri-PrCli-PrBri-PrCli-PrBri-PrCli-PrBri-Pr
Cln-BuBrn-BuCl n-BuBrn-BuCln-BuBrn-BuCln-BuBrn-Bu
Cli-BuBri-BuCli-BuBri-BuCli-BuBri-BuCli-BuBri-Bu
Cls-BuBrs-BuCls-BuBrs-BuCls-BuBrs-BuCls-BuBrs-Bu
Clt-BuBrt-BuClt-BuBrt-BuClt-BuBrt-BuClt-BuBrt-Bu

Table 2

Br
R1represents Cl
X represents NX represents CHX represents CClX represents CBr/td>
R2R3R2R3R2R3R2R3R2R3R2R3R2R3R2R3
ClHBrHClHBrHClHBrHClHBrH
ClMeBrMeClMeBrMeClMeBrMeClMeBrMe
ClEtBrEtClEtBrEtClEtBrEtClEtBrEt
Cln-PrBrn-PrCln-PrBrn-PrCln-PrBrn-Pr Cln-PrBrn-Pr
Cli-PrBri-PrCli-PrBri-PrCli-PrBri-PrCli-PrBri-Pr
Cln-BuBrn-BuCln-BuBrn-BuCln-BuBrn-BuCln-BuBrn-Bu
Cli-BuBri-BuCli-BuBri-BuCli-BuBri-BuCli-BuBri-Bu
Cls-BuBrs-BuCls-BuBrs-BuCls-BuBrs-BuCls-BuBrs-Bu
Clt-BuBrt-BuClt-BuBrt-BuClt-BuBrt-BuClBrt-Bu
R1is a Br
X represents NX represents CHX represents CClX represents CBr
R2R3R2R3R2R3R2R3R2R3R2R3R2R3R2R3
ClHBrHClHBrHClHBrHClHBrH
ClMeBrMeClMeBrMeClMeBrMeClMeBrMe
ClEtBrEtClEtBrEtCl EtBrEtClEtBrEt
Cln-PrBrn-PrCln-PrBrn-PrCln-PrBrn-PrCln-PrBrn-Pr
Cli-PrBri-PrCli-PrBri-PrCli-PrBri-PrCli-PrBri-Pr
Cln-BuBrn-BuCln-BuBrn-BuCln-BuBrn-BuCln-BuBrn-Bu
Cli-BuBri-BuCli-BuBri-BuCli-BuBri-BuCli-BuBri-Bu
Cls-BuBrs-BuCls-BuBrs-BuCls-Bus-BuCls-BuBrs-Bu
Clt-BuBrt-BuClt-BuBrt-BuClt-BuBrt-BuClt-BuBrt-Bu

Table 3

R2R3R2R3R2R3R2R3R2R3R2R3
ClHCln-PrCli-BuBrHBrn-PrBri-Bu
ClMeCli-PrCls-BuBrMeBri-PrBrs-Bu
ClEtCln-BuClt-BuBrEtBrn-BuBrt-Bu

p> Applicability

Compounds of formulas I, II, and 4 are suitable for use as synthetic intermediates for obtaining the compounds of formula III

where X, R1, R2and n are as defined above; R6represents CH3, Cl or Br; R7represents F, Cl, Br, I or CF3; and R8represents a C1-C4alkyl.

The compounds of formula III are suitable for use as insecticide.

The compounds of formula III can be obtained from compounds of formula II (and, in turn, compounds of formulas 4 and (I) using the methods depicted in schemes 5-7.

Connection pyrazolylborate acid of the formula IIa compound of formula II, where R3represents H) with Anthranilic acid of formula 5 gives benzoxazine formula 6. In scheme 5 benzoxazine formula 6 is prepared directly by successive addition methanesulfonyl chloride in the presence of a tertiary amine such as triethylamine or pyridine, to pyrazolylborate acid of the formula IIa, followed by the addition of Anthranilic acid of formula 5, followed by a second addition of tertiary amine and methanesulfonyl chloride. This procedure usually gives a good output of benzoxazinone.

Scheme 5

Scheme 6 depicts an alternative for obtaining benzoxazinones formula 6, including the connection of the acid chloride pyrazolones acid of formula 8 with anhydride stoneway acid of formula 7, with direct obtaining benzoxazinone formula 6.

Scheme 6

Solvent, such as pyridine or pyridine/acetonitrile are suitable for use in this reaction. The acid chlorides of formula 8 are available from the corresponding acids of formula IIa using known procedures such as chlorination using thionyl chloride or oxalicacid.

The compounds of formula III can be obtained by reacting benzoxazinones formula 6 with C1-C4bonds alkylamines, as depicted in scheme 7. The interaction can be performed by itself or in a variety of appropriate solvents, including tetrahydrofuran, simple, diethyl ether, dichloromethane or chloroform with optimum temperatures are in the range from room temperature to the temperature of reflux distilled solvent. The total interaction benzoxazinones with amines, with getting anthranilamide is well known in the chemical literature. Review of chemistry benzoxazinones see Jakobsen et al., Biorganic and Medicinal Chemistry 2000, 8, 2095-2103 and the references cited there. See also Coppola, J. Heteocyclic Chemistry 1999, 36, 563-588.

SCHEME 7

Example 17

Obtain 6,8-dichloro-2-[1-(3-chloro-2-pyridinyl)-3-bromo-1H-pyrazole-5-yl]-4H-3,1-benzoxazin-4-it

Stage A: Obtain 6,8-dichloro-2H-3,1-benzoxazin-2,4(1H)-dione

To a suspension of 2-amino-3,5-dichlorobenzoyl acid (104 g, 500 mmol), stir in dry dioxane (750 ml) at room temperature was added dropwise trichloromethylcarbonate (70 g, 350 mmol). The reaction mixture exothermically heated slowly up to 30°S, and the solid is almost completely dissolved before again to form a thick slurry. After stirring the suspension at ambient temperature for 2.5 hours specified in the title compound was isolated by filtration, washed with ethyl ether and dried to obtain specified in the connection header-product obtained as a white solid (82 g).

1H NMR (DMSO-d6) δ 7,88(d, 1H), 8,07 (d, 1H), and 11.6 (s, 1H).

Stage: Obtain 6,8-dichloro-2-[1-(3-chloro-2-pyridinyl)-3-bromo-1H-pyrazole-5-yl]-4H-3,1-benzoxazin-4-it

To a suspension of 1-(3-chloro-2-pyridinyl)-3-bromo-1H-pyrazole-5-carboxylic acid (i.e. the product of stage (C) (118 g, 390 mmol), stirred in dichloromethane (1 l)was added N,N-dimethylformamide (8 drops). Was added dropwise oxalicacid (63,8 g, 500 mmol) for 1.5 hours. The resulting solution was stirred at whom atoi temperature overnight and then concentrated in vacuum. The selected acid chloride acid was dissolved in dry acetonitrile (200 ml) was added to a suspension of 6,8-dichloro-2H-3,1-benzoxazin-2,4(1H)-dione (i.e. the product of stage (A) (82 g, 350 mmol), stir in dry acetonitrile (200 ml). Added pyridine (175 ml) and the solution was heated under reflux for reflux distilled for 4 hours. After cooling in a bath of ice collected precipitate white solid (152 g).

1H NMR (CDCl3) δ 7,27 (d, 1H), 7,38 (kV, 1H), 7,72 (s, 1H), 7,9 (d, 1H), with 8.05 (s, 1H), 8,55 (d, 1H).

Example 18

Getting 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-it

To a solution By solution methanesulfonanilide (and 0.40 ml, 5.2 mmol) in acetonitrile was added dropwise a mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (1.5 g, 4,96 mmol) and triethylamine (of 0.64 ml, 4,96 mmol) in acetonitrile at 0-5°C. Then the reaction temperature was maintained at 0°for the sequential addition of reagents. After stirring for 20 minutes was added 2-amino-3-methyl-5-chlorobenzoyl acid (0,92 g, 4,96 mmol) and stirring was continued for an additional 5 minutes. Then was added dropwise a solution of triethylamine (10.0 mmol) in acetonitrile and the reaction mixture was stirred for 45 minutes followed by the addition of methanesulfonanilide (and 0.40 ml, 5.2 mmol). Then the reaction mixtures is ü was heated to room temperature and was stirred overnight.

Got mentioned in the title compound as a solid (1,21 g).

1H NMR (CDCl3) δ a 2.01 (s, 3H), 7,29 (s, 1H), 7,42 (d, 1H), 7,95 (d, 1H), 8,04 (m, 1H), of 8.25 (s, 1H), compared to 8.26 (d, 1H).

Example 19

Obtain 3-bromo-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]-carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-it (i.e. the product of benzoxazinone obtained above) (0.20 g, 0.44 mmol) in tetrahydrofuran was added Isopropylamine (0,122 ml of 1.42 mmol) and the reaction mixture was heated to 60°C for 90 minutes and then cooled to room temperature. The solvent is tetrahydrofuran evaporated under reduced pressure and the remaining solid is triturated with ether, filtered and dried to obtain specified in the title compound, compounds of the present invention, in the form of a solid (150 mg), TPL 159-161°C.

1H NMR (CDCl3) δ 1,22 (d, 6N), are 2.19 (s, 3H), is 4.21 (m, 1H), of 5.99 (m, 1H), 7,05 (m, 1H), 7,22 (m, 2H), 7,39 (m, 1H), 7,82 (d, 1H), to 8.41 (d, 1H).

1. The compound of the formula I

where R1is a halogen;

R2represents halogen;

R3represents C1-C4alkyl;

X represents N or CH; and

n is 0-3, provided that when X isone SN, then n is at least 1.

2. The compound according to claim 1, where n is from 1 to 3.

3. The compound according to claim 1, where R1represents Cl or Br; each R2represents, independently, Cl or Br, and one of R2is in the 3rd position; and X represents N.

4. The method for obtaining the compounds of formula I according to claim 1, comprising processing the compounds of formula 4

where R3represents a C1-C4alkyl; halogenation agent.

5. The method according to claim 4 where n is from 1 to 3.

6. The method according to claim 4, where R1represents Cl or Br; each R2represents, independently, Cl or Br, and one of R2is in the 3rd position; R3represents a C1-C4alkyl; and X represents N.

7. The method according to claim 6, where the halogenation agent is oxychlorine phosphorus or pentavalent phosphorus.

8. The method according to claim 7, where the process is carried out in the absence of a base, using acetonitrile as a solvent.

9. The compound of formula II

where R1represents halogen;

R2represents halogen;

R3represents N or C1-C4alkyl;

X represents N or CH; and

n is from 0 to 3, provided that when X is predstavljaet a SN, then n is at least 1.

10. The connection according to claim 9, where n is from 1 to 3.

11. The connection according to claim 9, where

R1represents Cl or Br;

each R2represents, independently, Cl or Br, and one of R2is in the 3rd position; X represents N.

12. The connection according to claim 9, where n=1; R1represents Cl or Br;

R2represents Cl or Br, and R2is in the 3rd position and R3is N.

13. The compound of formula 4

where each R2represents halogen;

X represents N;

R3represents C1-C4alkyl; and

n is from 0 to 3.

14. The connection indicated in paragraph 13, where n is from 1 to 3.

15. The connection indicated in paragraph 13, where each R2represents, independently, Cl or Br, and one of R2is in the 3rd position.

16. The method of obtaining the compounds of formula II according to claim 9, including (3) treatment of compounds of formula I

oxidant optionally in the presence of acid to obtain the compounds of formula II; and when the compound of formula I, where R3represents a C1-C4alkyl, is used to produce the compounds of formula II, where R3represents H,

(4) converting the compound obtained in (3), connect the s formula II, where R3represents N.

17. The method according to clause 16, where n is from 1 to 3.

18. The method according to clause 16, where the oxidant is a peroxide or a persulfate salt.

19. The method according to p, where X represents CH; and the oxidizing agent is a peroxide.

20. The method according to p, where X represents N; the oxidizing agent is a potassium persulfate; and stage (3) is carried out in the presence of sulphuric acid.

21. The method according to clause 16, where in the formula I, where R1represents Cl or Br, each R2represents, independently, Cl or Br, and one of R2is in the 3rd position; R3represents a C1-C4alkyl; and X represents N.

22. The method according to clause 16, in which the compound of formula I obtained by the method comprising (1) treating compound of formula 4

where R3represents a C1-C4alkyl;

halogenation agent to obtain compounds of formula I.

23. The method of obtaining the compounds of formula III

where R1represents halogen;

each R2represents halogen;

X represents N or CH;

R6is CH3, Cl or Br;

R7represents F, Cl, Br, I or CF3;

R8is 1-C4alkyl and

n is 0, 1, 2 or 3; provided that when X represents CH, then n is at least 1;

using as intermediate compounds of formula II

where R3represents N;

characterized in that the method comprises the following stages:

(a) obtaining the compounds of formula II in accordance with the method described in article 16;

(C) obtaining the compounds of formula 6

or (i) by a combination of a compound II with the compound of the formula 5

or (ii) chlorination of compounds of formula II, receiving the compound of formula 8, and the combination of compounds of formula 8 with a compound of formula 7

(C) the interaction of the compounds of formula 6 with a compound of formula R8NH2.

24. The method according to item 23, where n is from 1 to 3.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of aminopyrrole of the formula (I): wherein each radical Ar1 and Ar2 means independently substituted phenyl, and each radical R1 and R2 means independently hydrogen atom, alkyl or a protective group at nitrogen atom, its isomer, mixtures of isomers, or its pharmaceutically acceptable salt. Also, invention relates to a pharmaceutical composition possessing anti-inflammatory activity. Also, invention comprises a method for synthesis of compounds of the formula (I), and using these compounds for preparing a medicinal agent used in treatment of inflammatory diseases in mammal, such as arthritis. Invention provides synthesis of novel compounds and preparing the pharmaceutical composition based on thereof.

EFFECT: improved method of synthesis, valuable medicinal property of compounds and pharmaceutical composition.

15 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, oncology, pharmacy, biochemistry.

SUBSTANCE: invention relates to amide derivative represented by the following formula [1]:

in any of the following cases (A) or (B), or its salt. In the case (A) R1 represents 5-7-membered saturated cyclic group comprising 1-2 nitrogen atoms as atom forming cycle (saturated cyclic amino-group can be substituted with 1-3 similar or different substitutes chosen from group consisting of (C1-C10)-alkyl, (C1-C10)-alkoxycarbonyl), mono-(C1-C10)-alkylamino- or di-(C1-C10)-alkylamino-group; R2 represents (C1-C10)-alkyl, halogen atom, halogen-(C1-C10)-alkyl, (C1-C10)-alkoxy-group, (C1-C10)-alkoxycarbonyl, nitro-group, mono-(C1-C10)-alkylcarbamoyl, di-(C1-C10)-alkylcarbamoyl or cyano-group; R3 represents hydrogen atom, halogen atom or (C1-C10)-alkoxy-group; Het1 represents any of the following formulae: [2] , [3] , [4] , [5] , [6] , [7] and [8] ; Het2 represents pyridyl, pyrimidinyl, pyrazinyl or 1,2-dihydropyridazinyl (wherein Het2 can be substituted with 1-3 similar or different substitutes chosen from halogen atom) but except for compound wherein R1 means (i) pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl and each of them can be substituted with 1-3 similar or different substitutes chosen from group consisting of alkyl, alkoxycarbonyl, halogen atom, halogenalkyl, hydroxyalkyl, amino-, monoalkylamino-, dialkylamino-group, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl; (ii) monoalkylamino-group, or (iii) dialkylamino-group; Het1 means group of the formula [6], and Het2 means pyrazinyl or pyridyl and each of them can mean a substituted alkyl. In case the (B) R1 represents 4-methylpiperazin-1-yl, 1-pyrrolidinyl, piperidino-group, 4-ethylpiperazin-1-yl, 4-n-propylpiperazin-1-yl, cis-3,5-dimethylpiperazin-1-yl, morpholino-, dimethylamino- or diethylamino-group; R2 represents methyl, halogen atom, trifluoromethyl, methoxy-group, methoxycarbonyl, nitro-group, dimethylcarbamoyl or cyano-group; R3 represents hydrogen atom, bromine atom or methoxy-group; Het1 represents compound of the formula [6]; Het2 represents 3-pyridyl. Invention relates to a pharmaceutical composition possessing inhibitory activity with respect to BCR-ABL tyrosine kinase comprising amide derivative of the formula (I) or its salt as active component and a pharmaceutically acceptable nontoxic and inert carrier. Also, invention relates to BCR-ABL tyrosine kinase inhibitor, therapeutic agents comprising amide derivative of the formula (I) or its salt and, optionally, a pharmaceutically acceptable nontoxic and inert carrier used in treatment of chronic myelogenous leukemia, acute lymphoblast cell leukemia, acute myelogenous leukemia. Invention provides and proposes amide derivative inhibiting activity of BCR-ABL tyrosine kinase.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 2 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 2-hetaryl-substituted derivatives of 1,2-tropolones of the general formula (Ia): wherein R1 and R2 mean (C1-C6)-alkyl; R3 means hydrogen atom, (C1-C6)-alkyl, nitro-group; Het means six-membered nitrogen heterocycle condensed with one or two benzyl rings that can be substituted with substitutes chosen from group comprising halogen atom, nitro-group, (C1-C6)-alkyl, oxy-(C1-C6)-alkyl, secondary amino-group chosen from anilino-, substituted anilino-, hydroxyethylamino-group, or tertiary amino-group chosen from morpholino-, piperidino-, piperazino-group, 1H-1-imidazolyl. Also, invention relates to a method for synthesis of 2-hetaryl-substituted derivatives of 1,3-tropolone. Method involves condensation of benzoquinones-1,2 with 2-methylheterocycles at heating in the presence of acetic acid taken in the amount providing its role as both a catalyst and a solvent. Also, invention relates to a pharmaceutical composition with antibacterial effect based on 2-hetaryl-substituted derivatives of 1,3-tropolone.

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

9 cl, 5 tbl, 3 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel derivatives if 1,3,5-triazine of the general formula (1): wherein R1 means halogen atom, (C1-C3)-alkyl, (C1-C3)-alkoxy-group, N-(di)-(C1-C3)-alkyl, NH-(C2-C3)-alkynyl, N,N-(C1-C3)-alkyl, (C2-C3)-alkynyl or 1-pyrrolidinyl, 1-piperidinyl or 1-morpholinyl group; R2 means hydrogen atom (H), (C1-C3)-alkyl possibly substituted with hydroxy-, (C1-C3)-alkoxy- or phenoxy-group; R3 means H, -CF3, (C1-C3)-alkyl possibly substituted with hydroxy-, (C1-C3)-alkoxy-, phenoxy-group or 1-morpholinyl group; or R2 and R3 in common with phenyl group to which they are bound form benzodioxolane or naphthalene cyclic system; R4 means H, -CF3 or (C1-C3)-alkoxy-group; X means -NH, N-(C1-C3)-alkyl, -CH2, oxygen atom (O) or a bond carbon-carbon; Y means group of the general formula (A) , (B) or (C) wherein R5 means -OH or -CH2OH; R6 means H or phenyl; n = 0 or 1; R7 means (C1-C3)-alkyl; R8 means H, -OH or (C1-C3)-alkoxy-group; R9 means H or (C1-C3)-alkoxy-group; R10 and R11 mean independently H or (C1-C3)-alkyl; Z means -NOH or O, or their pharmacologically acceptable salts, pharmaceutical composition possessing (ant)agonistic activity to adenosine-A3 receptors and using novel compounds in treatment of such diseases as chronic pains, arthritis, cerebrospinal sclerosis, asthma, psoriasis and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 4 tbl, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a compound of the formula (I): , wherein carbon atom designated as * is in (R)- or (S)-configuration; R1 represents (C1-C6)-alkyl; R2 represents hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-halogenalkyl; R3 represents H or halogen atom; R4 represents phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, isoxazolyl, pyrazolyl or pyrazinyl wherein R4 group is substituted optionally with 1-4 R14-substitutes; each among R5, R6 and R7 is chosen independently from the following group: H, halogen atom, -OR11, -CN, (C1-C4)-halogenalkyl or (C1-C6)-alkyl; or R5 and R6 taken in common can represent -O-C-(R12)2-O-; R8 represents H; R11 represents H or (C1-C4)-alkyl; R12 represents (C1-C4)-alkyl; R12 is chosen independently in each case from a substitute chosen from the following group: halogen atom, -OR11, -NR11R12, morpholinyl, (C1-C6)-alkyl and (C1-C4)-halogenalkyl, or its pharmaceutically acceptable salt or solvate. Also, invention describes a pharmaceutical composition used in blocking in reuptake of norepinephrine, dopamine and serotonin based on compounds of the formula (I). Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties, improved method of treatment.

39 cl, 2 tbl, 49 ex

FIELD: organic chemistry.

SUBSTANCE: described is 3-phenylsulfonyl-8-piperazin-1-yl-quinoline of formula I or pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen or C1-C6-alkyl, or R1 and R2 together form group (CH2)2, (CH2)3 or (CH2)4; R3, R4 and R5 are hydrogen, halogen or C1-C6-alkyl; m = 1-4; n = 1-3; A is -Ar1, Ar1 is optionally substituted with 1 or more substituents. Disclosed are four methods for production of abovementioned compounds.

EFFECT: new compounds with affinity to 5-HT6 receptor.

23 cl, 5 tbl, 52 ex, 6 dwg

FIELD: organic chemistry, medicine, neurology, biochemistry, pharmacy.

SUBSTANCE: invention relates to a group of novel compounds of the formula (1): wherein S1 represents, hydrogen, halogen atom; S3 represents halogen atom; X represents nitrogen or carbon atom; Y represents nitrogen or oxygen atom when X represents nitrogen atom, or Y represents nitrogen atom when X represents carbon atom; R5 represents hydrogen atom or (C1-C6)-alkyl; R6 represents hydrogen atom or (C1-C3)-alkyl; R7 represents hydrogen atom or (C1-C3)-alkyl; Z1, Z2 and Z3 represent carbon atom, or Z1 represents nitrogen atom, and Z2 and Z3 represent carbon atom; or Z1 and Z3 represent carbon atom; Z2 represents nitrogen atom; or Z1 and Z2 represent carbon atom, and Z3 represents nitrogen atom; A represents (poly)cycloalkyl system consisting of (4-10)-membered rings that can be substituted with alkyl or -CN, and its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition and using compounds based on the formula (1) possessing inhibitory activity with respect to enzymes that cleave a neuropeptide neurotensin. Invention provides synthesis of novel biologically active compounds and pharmaceutical composition based on thereof that possess inhibitory activity with respect to enzymes destructing a neuropeptide neurotensin.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical compositions.

4 cl, 4 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions possessing inhibitory effect with respect to MC2R-receptors, for preparing medicinal preparations as tablets, granules, capsules, suspensions, solutions or injections placed into pharmaceutically acceptable package. As active substance the composition comprises azaheterocyclic compound of general formulas (1.1.1) , (1.2.1) or (1.3.1) , wherein R1 in the general formula (1.1.1) represents substituted alkyl, aryl, heteroaryl, heterocyclyl, or R1 in the general formula (1.2.1) represents a substitute of amino-group chosen from hydrogen atom or possibly substituted lower alkyl or lower acyl; each R2, R3 and R4 represents independently of one another a substitute of cyclic system chosen from hydrogen atom, azaheterocyclyl, possibly substituted lower alkyl, possibly substituted hydroxy-group, carboxy-group, cycloalkyl; or R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle, or R1 in common with nitrogen atom to which it is bound, and R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle through R1, R3 and R4; R18 and R19 represent independently of one another substitutes of amino-group chosen from hydrogen atom or lower alkyl substituted with azaheterocycle as their racemates, optically active isomers or their pharmaceutically acceptable salts and/or hydrates; R20 and R21 in common with nitrogen atom to which they are bound form possibly substituted azaheterocycle. Also, invention relates to a method for preparing a pharmaceutical composition and using compounds and compositions for preparing medicinal preparations and for treatment or prophylaxis of diseases associated with enhanced activation of adrenocorticotropic hormone for compounds of general formulas (1.1.1), (1.2.1) and (1.3.1), and for using compounds for experimental investigations of indicated processes in vitro or in vivo also.

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

15 cl, 1 dwg, 4 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (IA) or (IB) given in the invention description wherein R1 means hydrogen atom, (C1-C7)-alkyl, -(CH2)n-OH, -(CH2)n-N(R6)2; R2 means (C1-C7)-alkyl, -(CH2)n-N(R6)2, -NR6C(O)C(O)O-(C1-C7)-alkyl, -NR6-(CH2)n-OH, -NR6C(O)-(C1-C7)-alkyl, -NH-benzyl; R3 means hydrogen atom or amine; or R2 and R3 in common with carbon atoms to which they are bound mean the group -N(R6)-CH2-O-CH2-; R4 means hydrogen atom or (C1-C7)-alkyl; R5 means hydrogen atom; R6 means independently of one another hydrogen atom or (C1-C7)-alkyl; R' means hydrogen atom or (C1-C7)-alkyl; n = 0, 1, 2 or 3. Also, invention relates to a medicinal agent possessing the selective blocking activity with respect of subspecies of NMDA-receptors and containing one or more compounds of the formula (IA) or (IB) or their pharmaceutically acceptable acid-additive salt or inert carrier. Invention provides preparing novel compounds possessing the high affinity to NMDA-receptors that can be used as components of a medicinal agent for treatment of diseases mediated by these receptors.

EFFECT: valuable medicinal properties of compounds and drug.

13 cl, 35 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of adamantine, in particular, to a new method for preparing adamant-1-yl-containing azoles of the general formula I-VIII: wherein R1 means ; R2 means ; R3 means ; R4 means ; R5 means ; R6 means ; R7 means , and R8 means . Indicated derivatives of adamantine are semifinished products used in synthesis of biologically active substances. Proposed method for preparing these compounds involves using a new method for synthesis of adamant-1-yl-containing azoles that includes the addition reaction of azoles: 2-methylimidazole, 3(5)-methylpyrazole and 4-methylpyrazole, 3,4-dinitropyrazole, 1,2,4-triazole, 3-methylpyrazole, 3-nitro-1,2,4-triazole and 5-methyltetrazole to 1,3-dehydroadamantane in the mole ratio of 1,3-dehydroadamantane to azole = 1:1 in diethyl ether medium at temperature 100°C for 4-5 h.

EFFECT: improved preparing method.

8 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

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

7 cl, 6 tbl, 3 ex

The invention relates to biphenylamine General formula I

< / BR>
and their salts, where R1means H or F; R2means H, halogen, C1-C4-alkyl; R3means of CH3; connection I use for combating phytopathogenic fungi

The invention relates to new derivatives of 1-methyl-5-chloropyrazole General formula where R is CH2Cl, CF3, 4-CLC6H4, 3-NO2C6H4that shows antibacterial activity

The invention relates to a derivative of a simple ester, application and intermediate compounds used for their production

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

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