Method of 3-halogen-4,5-dihydro-1h pyrasol preparation

FIELD: chemistry.

SUBSTANCE: invention refers to the method of preparation of 3-halogen-4.5-dihydro-1H-pyrasol compound of the formula , it includes interreaction with HX1of other 4.5-dihydro-1H-pyrasol compound of the formula , in which X1 is halogen and R3, R4, Z, n and X2 have values given in the description. The invention also describes preparation of the compounds of the formula , in which X1, R3, R6, R7, R8a, R8b and n have values, which are indicated in the description, in terms of the formula (Ia) of the compound, prepared according to p.1 of the invention formula.

EFFECT: development of the alternative method of preparation of the compounds with using reagent of relatively low price.

9 cl, 1 tbl, 4 ex, 9 dwg

 

BACKGROUND of INVENTION

There is a need for additional methods for the preparation of 3-halo-4,5-dihydro-1H-pyrazoles. Such compounds include intermediate compounds, suitable for protection of agricultural crops, pharmaceuticals and other compounds, products of fine chemical technology.

It was reported about several methods for the preparation of 3-halo-4,5-dihydro-1H-pyrazoles. For example, J.P. Chupp, J. Heterocyclic Chem. 1994, 31, 1377-1380, reports a 3-chloro-4,5-dihydro-1H-pyrazole by reacting the corresponding oxadiazolidine with phosphorus oxychloride. M.V. Gorelic et al., Journal of Organic Chemistry USSR, 1985, 21, 773-781 (English Translation of the Journal of organic chemistry 1985, 21(4), 851-859) describe the 3-chloro-4,5-dihydro-1H-pyrazoles via intermediate compounds, diazonium salts derived from the corresponding 3-amino-4,5-dihydro-1H-pyrazoles. K.K. Bach et al., Tetrahedron 1994, 50(25), 7543-7556 describe how to obtain 3-chloro-4,5-dihydro-1H-pyrazole by bipolar cycloaddition acrylate of ester intermediate compound - hydridoborate resulting from decarboxylases chlorination of hydrazone Glyoxylic acid using N-chlorosuccinimide. There remains a need for alternative methods, especially with General applicability for a wide range of chemical is of such structures, and when used reagents with relatively low cost, available for purchase in industrial quantities.

SUMMARY of INVENTION

This invention relates to a method for the preparation of 3-halo-4,5-dihydro-1H-pyrazol the compounds of formula I

where L is a possibly substituted carbon group;

each R is independently selected from a possibly substituted carbon groups;

k is an integer from 0 to 4;

and X1is halogen.

The method includes the interaction 4,5-dihydro-1H-pyrazol the compounds of formula II

where X2is OS(O)mR1, OP(O)p(OR2)2or halogen other than X1;

m is 1 or 2;

p is 0 or 1;

R1selected from alkyl and halogenoalkane; and phenyl possibly substituted from 1 to 3 substituents selected from alkyl and halogen; and

each R2independently selected from alkyl and halogenoalkane; and phenyl possibly substituted from 1 to 3 substituents selected from alkyl and halogen, with a compound of the formula HX1in the presence of a suitable solvent.

This invention relates also to a method for obtaining compounds of formula III,

where

X1is halogen,

each R3 independently represents C1-C4alkyl, C2-C4alkenyl,2-C4quinil,3-C6cycloalkyl,1-C4halogenated,2-C4halogenoalkanes,2-C4halogenoalkanes,3-C6halogenosilanes, halogen, CN, NO2With1-C4alkoxy, C1-C4halogenoalkane,1-C4alkylthio,1-C4alkylsulfonyl,1-C4alkylsulfonyl, C1-C4alkylamino,2-C8dialkylamino,3-C6cyclooctylamino, (C1-C4alkyl)(C3-C6cycloalkyl)amino, C2-C4alkylsulphonyl,2-C6alkoxycarbonyl,2-C6alkylaminocarbonyl,3-C8dialkylaminoalkyl or3-C6trialkylsilyl;

Z is N or CR5;

R5represents N or R3;

R6is CH3, F, Cl or Br;

R7represents F, Cl, Br, I or CF3;

R8Ais1-C4alkyl;

R8brepresents N or CH3; and

n is an integer from 0 to 3

with the use of the compounds of formula Ia

where R4is H or possibly substituted carbon group.

This method is obtaining the compounds of formula a (i.e. subspecies of formula (I) by the method given above.

DETAILED description of the INVENTION

Here in the description, the term "carbon group" refers to a radical in which a carbon atom is connected with the main structure of 4,5-dihydro-1H-pyrazol ring. As carbon groups L and R (including R4) substituents are separated from the reaction center, they can cover a large number of groups on the basis of carbon produced modern methods of organic chemistry synthesis. The method of this invention generally is applicable to a wide range of starting compounds of the formula I and compounds of the product of formula II. The person skilled in the art will understand that certain groups are sensitive to the hydrogen halides and can be transformed under certain reaction conditions. The person skilled in the art will also understand that some groups are basic and can form salts with hydrogen halides and, thus, with the method of the present invention may additionally require the hydrogen halide.

"Carbon group", therefore, includes alkyl, alkenyl and quinil, which may be straight or branched chain. "Carbon group" includes carbocyclic and heterocyclic rings which may be saturated, partially saturated or fully narasiman the mi. In addition, the unsaturated rings may be aromatic, if you meet the hückel rule. Carbocyclic and heterocyclic rings carbon group may form a polycyclic ring system, consisting of multiple rings connected with each other. The term "carbocyclic ring" means a ring, in which the atoms forming the basic ring structure selected only from carbon. The term "heterocyclic ring" denotes a ring system, in which at least one of the atoms of the ring structure is other than a carbon atom. "Saturated carbocyclic" refers to a ring having a main chain consisting of carbon atoms linked together by single bonds; unless otherwise specified, the remaining valencies of carbon are occupied by hydrogen atoms. The term "aromatic ring system" denotes fully unsaturated carbocycles and heterocycles in which at least one ring in the polycyclic ring system is aromatic. The term "aromatic" indicates that each of the atoms in the ring is essentially in the same plane and has ap-orbital perpendicular to the plane of the ring, and in which (4n+2)π electrons, when n is 0 or a positive integer, United in a ring, in compliance and with the hückel rule. The term "aromatic carbocyclic ring system" includes fully aromatic carbocycle and carbocycle, in which at least one cycle of the polycyclic ring system is aromatic. The term "nonaromatic carbocyclic ring system" denotes fully saturated carbocycle, as well as partially or fully unsaturated carbocycle in which any one of the rings in the ring system is not aromatic. The terms "aromatic heterocyclic ring system" and "heteroaromatic ring" includes fully aromatic heterocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic. The term "non-aromatic heterocyclic ring system" denotes fully saturated heterocycle, and a partially or fully saturated heterocycle, in which any one of the rings in the ring system is not aromatic. The term "aryl" means a carbocyclic(th) or heterocyclic(th) ring or rings, in which at least one ring is aromatic, and the aromatic ring provides connectivity with the rest of the molecule.

The carbon group described for L, R, and R4are possibly substituted. The term "possibly substituted" in relation to acicularity groups refers to carbon groups which are unsubstituted or have at least one non-hydrogen Deputy. Illustrative optional substituents include alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, hydroxycarbonyl, formyl, alkylsulphonyl, alkenylboronic, alkynylaryl, alkoxycarbonyl, hydroxy, alkoxy, alkenylacyl, alkyloxy, cycloalkane, aryloxy, alkylthio, alkanity, alkylthio, cycloalkyl, aaltio, alkylsulfonyl, alkanesulfonyl, alkylsulfonyl, cycloalkylcarbonyl, arylsulfonyl, alkylsulfonyl, alkanesulfonyl, alkylsulfonyl, cycloalkylcarbonyl, arylsulfonyl, amino, alkylamino, alkynylamino, alkynylamino, arylamino, aminocarbonyl, alkylaminocarbonyl, alkenylamine, alkylaminocarbonyl, allumination, alkylaminocarbonyl, alkenylamine, alkylaminocarbonyl, allmenareliars, alkoxycarbonyl, alkanolammonium, alkyloxycarboxylic, aryloxypropanolamine, each of which, moreover, is a possibly substituted; and halogen, cyano and nitro. Optional substituents independently chosen from groups, such as those presented above with respect to the substituents of additional replacement groups for L, R, and R4such as halogenated, halogenoalkanes, halogenoalkane. As the additional example of alkylamino may be optionally substituted by alkyl, giving dialkylamino. The substituents may be linked together by removing one or two hydrogen atoms from each of two Deputy or Deputy and maintain the molecular structure and bonding radicals with obtaining cyclic and polycyclic structures, condensed molecular structure or attached to the molecular structure, bearing substituents. For example, linking together adjacent hydroxy and methoxypropyl attached to, for example, phenyl ring, gives a condensed dioxolane structure containing linking group,- O-CH2-O-. Linking together hydroxyl groups and molecular structure, with which it is connected, can give cyclic ethers, including epoxides. Illustrative substituents include oxygen, which, when it is attached to the carbon forms a carbonyl group. Similarly, sulfur, when it is connected with the carbon to form a thiocarbonyl group. In the carbon group L or R linking substituents together may give cyclic and polycyclic structures. Also for illustrative carbon groups L and R are embodiments in which at least two groups R or the group L, and at least one group R is included in one and the same radical (i.e. forms a ring system). When formed and 4,5-dihydropyrazolo group one ring, two adjacent groups R or groups L and R, prisoners in the same radical, would result in a condensed bicyclic or polycyclic ring system. Two pair hosted a group R, prisoners in the same radical, would result in spiracular system.

In accordance with the description of "alkyl", used alone or in compound words such as "alkylthio" or "halogenated"includes alkyl straight or branched chain such as methyl, ethyl, n-propyl, isopropyl or the different butyl isomers, pentile or exile. The term "1-2 alkyl" indicates that one or two of the possible positions for this substituent can be alkilani, which are selected independently. "Alkenyl includes alkenes with a straight or branched chain, such as ethynyl, 1-propenyl, 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 ethinyl, 1-PROPYNYL, 2-PROPYNYL and the different isomers of butenyl, pentenyl and hexenyl. "Quinil may also include groups containing multiple triple bond, such as 2,5-hexadienyl. "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropoxy and various isomers of butoxy, pentox, hexyloxy. "Alkenylacyl" includes alkenylacyl the group with straight and branched chain. Examples of "alkenylacyl" include N2C=SNSN2Oh, (CH3)2C=SNSN2Oh, (CH3)SN=SNSN2Oh, (CH3)CH=C(CH3)CH2Oh and CH2=SNSN2CH2O. "Alkyloxy" includes groups with straight or branched chain. Examples of "alkyloxy include the NA≡CLO2O, CH3With≡CLO2Oh and CH3With≡CLO2CH2O. "Alkylthio" includes ancilliary straight or branched chain, such as methylthio, ethylthio and different isomers of property, butylthio, pentylthio and hexylthio. "Alkylsulfonyl" includes both enantiomers alkylsulfonyl group. Examples of "alkylsulfonyl" include CH3S(O), CH3CH2S(O), CH3CH2CH2S(O), (CH3)2CHS(O) and the various isomers of butylsulfonyl, pentasulfide and hexylaniline. Examples of "alkylsulfonyl" include CH3S(O)2CH3CH2S(O)2CH3CH2CH2S(O)2, (CH3)2CHS(O)2and various isomers butylsulfonyl, pentasulphide and hexylsilane. "Alkylamino", "alkanity", "alkanesulfonyl", "alkanesulfonyl", "alkylthio", "alkylsulfonyl" and "alkylsulfonyl" and the like have definitions similar to the above examples. Examples of "alkylcarboxylic" include C(O)CH3With(About)sub> 2CH2CH3and C(O)CH(CH3)2. Examples of alkoxycarbonyl include CH3OS(=O), CH3CH2OS(=O), CH3CH2CH2OS(=O), (CH3)2DEMOLITION(=O) and the different isomers of butoxy or phenoxycarbonyl. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkane" includes the same groups linked through an oxygen atom, such as cyclopentyloxy, cyclohexyloxy. "Cycloalkenyl" means the nitrogen atom of the amino group, which is associated with cycloalkyl radical and a hydrogen atom and includes such groups as cyclopropylamino, cyclobutylamine, cyclopentylamine, cyclohexylamine. (Alkyl)(cycloalkyl)amino" means cycloalkylation, where the hydrogen atom is replaced by an alkyl radical; examples include groups such as (methyl)(cyclopropyl)amino, (butyl)(cyclobutyl)amino, (propyl)cyclopentylamine, (methyl)cyclohexylamino and the like. "Cycloalkenyl" includes such groups as cyclopentenyl and cyclohexenyl, as well as groups with more than one double bond, such as 1,3 - and 1,4-cyclohexadienyl.

The term "halogen", or separately, or in compound words such as "halogenated"includes fluorine, chlorine, bromine or iodine. The term "1-2 halogen" means that one or two of the possible positions for this Deputy may be Gal is gene selected independently. In addition, when it is used in compound words such as "halogenated"specified alkyl may be partially or completely replaced by halogen atoms that can be the same or different. Examples of "halogenoalkane" include F3With ClCH2, CF3CH2and CF3CCl2.

The total number of carbon atoms in the group substituent shown by the prefix "Ci-Cj"where i and j are, for example, numbers from 1 to 3; for example, With1-C3alkyl means a radical with bromide in cut.

Although there is no specific limitation on the sizes of formulas I and II are suitable for methods of the present invention, usually the formula II includes 4-100, more usually 4-50, and most usually, 4-25 carbon atoms, and 3-25, more typically from 3 to 15, and most typically, 3-10 heteroatom(s). Heteroatoms typically selected from halogen, sulfur, nitrogen and phosphorus. Two heteroatoms in formulas I and II are nitrogen atoms dihydropyrazolo ring; X1is a halogen, and X2will contain at least one heteroatom.

Although there is no exact limit of size L and R (including R4), possibly substituted alkyl groups in L and R (including R4) typically contain from 1 to 6 carbon atoms, more usually from 1 to 4 carbon atoms, and most typically from 1 to 2 carbon atoms in the alkyl chain. POS is but substituted alkeneamine and alkyline group in L and R (including R 4) typically contain from 2 to 6 carbon atoms, more usually from 2 to 4 carbon atoms, and most typically from 2 to 3 carbon atoms in alkenylphenol or alkenylphenol chain.

Also there is no exact limit the size of the groups listed in the relation R1and R2but alkyl, including derivatives such as alkoxy and halogenated, usually presents With1-C6more typically1-C4and most usually With1-C2.

As indicated above, the carbon group L, R, and R4can be (among other things) an aromatic cycle or a ring system. Examples of aromatic cycles cycles or systems include phenyl ring, a 5 - or 6-membered heteroaromatic cycles, 8-, 9 - or 10-membered condensed carbocyclic ring system, and an aromatic 8-, 9 - or 10-membered condensed heterobicyclic ring system, in which each cycle or cycle system is a possibly substituted. The term "possibly substituted" in connection with the data L and R carbon to carbon groups include groups which are unsubstituted or have at least one non-hydrogen Deputy. These carbon groups can be substituted possibly as many deputies as may be accommodated by replacing hydrogen atoms non-hydrogen Deputy at any available atom coal is an ode or a nitrogen atom. Usually the number of possible substituents (when they are present) is in the range from one to four. Example phenyl, possibly substituted by one to four substituents is the ring illustrated as U-1 in list 1, where Rvis any non-hydrogen Deputy, and r is an integer from 0 to 4. Examples of 8-, 9 - or 10-membered condensed carbocyclic ring systems, possibly substituted by one to four substituents include naftalina group, possibly substituted by one to four substituents, represented as U-85, and 1,2,3,4-tetrahydronaphthalene group, possibly substituted by one to four substituents, represented as U-86 in the list of alternates 1, where Rvis any Deputy, and r is an integer from 0 to 4. Examples of 5 - or 6-membered heteroaromatic cycles, possibly substituted by one to four substituents include cycles with U-2 through U-53, presented in list 1, where Rvis any Deputy, and r is an integer from 0 to 4. Examples of aromatic 8-, 9 - or 10-membered condensed heterobicyclic ring systems, possibly substituted by one to four substituents include U-54 U-84, presented in list 1, where Rvis any Deputy, and r is an integer from 0 to 4. Other examples L and R in luchot benzyl group, possibly substituted by one to four substituents, represented as U-87, and benzoyloxy group, possibly substituted by one to four substituents, represented as U-88 in list 1, where Rvis any Deputy, and r is an integer from 0 to 4.

Although Rvthe group is represented in structures with U-1 U-85, note that there is no need for their presence, since they are optional substituents. The nitrogen atoms that require substitution to fill their valence, substituted N, or Rv. It should be noted that some of U groups can be substituted only less than 4 groups of Rv(for example, U-14, U-15, U-18, U-21 and U-32 U-34 can be replaced by only one Rv). It should be noted that when the connection between (Rv)rand U group is shown as changeable, (Rv)rcan be attached to any available carbon atom or nitrogen atom of the group U. When the connection to the group U is shown as changeable, the group U can be attached to the rest of the structure of formulas I and II through any available carbon atom of the group U by replacing a hydrogen atom.

As indicated above, the carbon group L, R, and R4can be (among others) n is sidename or partially saturated carbocyclic and heterocyclic rings, optionally substituted. The term "possibly substituted" in connection with these L and R carbon to carbon groups include groups which are unsubstituted or have at least one non-hydrogen Deputy. These carbon groups can be substituted possibly as many deputies as may be accommodated by replacing hydrogen atoms non-hydrogen Deputy at any available carbon atom or nitrogen. Typically, the number of substituents possible (when they are present) ranges from one to four. Examples of saturated or partially saturated carbocyclic rings include possibly substituted C3-C8cycloalkyl and possibly replaced With3-C8cycloalkyl. Examples of saturated or partially saturated heterocyclic rings include 5 - or 6-membered non-aromatic heterocyclic ring, possibly including one or two ring residue selected from the group consisting of C(=O), SO or S(O)2possibly substituted. Examples of such L-and R-carbon groups include groups represented in the form G-1 through G-35 in list 2. It should be noted that when the place of attachment of these G groups is shown as changeable, the group G can be connected with the rest of the structures of formulas I and II through any available carbon atom or nitrogen group G by replacing the atom in which Orada. Possible substituents can be joined with any possible atom of carbon or nitrogen by replacement of a hydrogen atom (these substituents are not shown in list 2, since they are optional substituents). It should be noted that when G consists of a ring selected from groups G-24 G31, G-34 and G-35, Q2can be selected from O, S, NH or substituted n

It is noted that the carbon group L, R, and R4can be substituted. As noted above, the carbon group L and R may typically include, among other groups, the group U or G, optionally substituted from one to four substituents. Thus, the carbon group L and R can consist of a U or G is selected from U-1 through U-88 or G-1 through G-35, and additionally substituted by additional substituents, including from one to four groups U or G (which may be the same or different), and as the main group U or G, and substituting U or G is optionally substituted. It should be noted carbon group L containing U, possibly substituted from one to three additional substituents. For example, L can be U-41.

As shown in figure 1, in accordance with the method of the present invention 4,5-dihydro-1H-pyrazole of the formula II lead in the interaction with the HX1 with the formation of another 3-halo-4,5-dihydro-1H-pyrazol the compounds of formula I.

Scheme 1

where L, R, X1X2and k have the meanings specified in section "Summary of invention".

The reaction is carried out in a suitable solvent. For best results, the solvent shall be dinucleophiles, relatively inert NC1and capable of dissolving the compounds of formula II. Suitable solvents include dibromomethane, dichloromethane, acetic acid, ethyl acetate and acetonitrile. The reaction can be conducted at atmospheric pressure or close to it or at a pressure above atmospheric in the pressure vessel. The original substance NC1you can add in the form of gas in the reaction mixture containing the compound of formula II and the solvent. When X2in the compound of formula II is halogen, such as Cl, the reaction is preferably carried out in such way that NC2generated during the reaction is removed by sparging or other appropriate means. Alternatively, the original substance NC1may be first dissolved in an inert solvent in which it has a high solubility (such as acetic acid) before interaction with the compound of the formula II or in pure form or in solution. And also, when X2in connected and formula II is halogen, such as CL, it is usually necessary on the merits of more than one equivalent of HX1(for example, from 4 to 10 equivalents), depending on the level of the desired transformation. One equivalent of HX1can provide high transformation when X2is OS(O)mR1or OP(O)p(OR2)2but when the compound of formula II contains at least one alkaline functional groups (i.e. those containing a nitrogen heterocycle), usually need more than one equivalent of HX1. The reaction can be carried out when a temperature of between about 0 and 100°With, most conveniently at about ambient temperature (e.g., about 10-40°and most preferably between about 20 and 30°C. the Addition of the catalyst, Lisovoy acid (for example, aluminum bromide, to obtain the compounds of formula I, where X1is Br)can facilitate the reaction. The product of formula I produce with conventional methods, known in the art, including extraction, distillation and crystallization.

For the method of this invention, the preferred starting compound include the compounds of formula II where m is 2 and p is 1. Also preferred are the starting compounds of formula II, where X2is halogen or OS(O)mR1(especially when m is 2). In addition, preferred are the camping source the compounds of formula II, where X2represents Cl or OS(O)mR1, m is 2, and R1represents a C1-C6alkyl, CF3or phenyl, possibly substituted from 1 to 3 substituents selected from C1-C4of alkyl, and more preferably, when R1is1-C2alkyl, phenyl or 4-were. Particularly preferred methods of this invention include those in which the use of a starting material of the formula II, where X2represents Cl or OS(O)2R1and R1represents methyl, phenyl or 4-were. Particularly preferably, when the method of this invention using a starting material of formula II, where X2represents Cl or OS(O)2R1and R1represents phenyl or 4-were.

For the method of the present invention preferred compounds of the product include the compounds of formula I, where X1is Cl, Br or I. preferred compounds of the product include the compounds of formula I, where X1is Cl or Br. The most preferred compounds of the product include the compounds of formula I, where X1is Br. Particularly successful embodiment of the method of the present invention include obtaining the compounds of formula I, where X1is Cl or Br, of the compounds of formula II, where X2is OS(O)2R1where R1pre is is, for example, methyl, phenyl or 4-were, more preferably, phenyl or 4-were.

Preferred methods of this invention include the way in which the original compound of formula II is a compound of formula IIa and the product, compound of formula I is a compound of formula Ia, as shown in scheme 2, below.

Scheme 2

where X1and X2have the meanings specified for formula I and II;

each R3, independently, is C1-C4alkyl, C2-C4alkenyl,2-C4quinil,3-C6cycloalkyl,1-C4halogenated,2-C4halogenoalkanes,2-C4halogenoalkanes,3-C6halogenosilanes, halogen, CN, NO2With1-C4alkoxy, C1-C4halogenoalkane,1-C4alkylthio,1-C4alkylsulfonyl,1-C4alkylsulfonyl, C1-C4alkylamino,2-C8dialkylamino,3-C6cyclooctylamino, (C1-C4alkyl)(C3-C6cycloalkyl)amino, C2-C4alkylsulphonyl,2-C6alkoxycarbonyl,2-C6alkylaminocarbonyl,3-C8dialkylaminoalkyl or3-C6trialkylsilyl;

R4represents H or POS is but substituted carbon residue;

Z is N or CR5;

R5represents N or R3; and

n is an integer from 0 to 3.

The expert will understand that the formula Ia is a subspecies of formula I and formula IIa is a subspecies of the formula II.

Although a wide range of possible substituted carbon groups that already described, suitable as R4in the esters of formula Ia for the method according to the scheme 2, usually R4is a radical containing up to 18 carbon atoms and selected from alkyl, alkenyl and quinil; and benzyl and phenyl, each of which may substituted by alkyl and halogen. Most preferably, when R4is1-C4the alkyl.

It should be noted the method presented in scheme 2, where Z is N, n is 1 and R3is Cl or Br and a is a 3-position. Also of note is the method presented in scheme 2, wherein X2is halogen or OS(O)2R1especially, when R1is stands, phenyl or 4-were. Also noteworthy is the method shown in scheme 2, when X1is Br or Cl, and especially when X1is Br. Especially noteworthy is the way presented in figure 2, when X1is Br, X2is Cl or OS(O)mR1, m is 2, and R1is phenyl or 4-were.

When prisutstvuet is the main functional group in the compound of formula IIa (for example, Z is N, and/or R3is alkylamino, dialkylamino, cyclooctylamino or (alkyl)(cycloalkyl)amino)usually need more than one equivalent of HX1for satisfactory conversion, even when X2is a OS(O)mR1or OP(O)p(OR2)2. When Z is N, R3is another group, not alkylamino, dialkylamino, cyclooctylamine and (alkyl)(cycloalkyl)amino), and X2is S(O)2R1in formula IIa, a high degree of transformation achieved using such a small amount NC1as from 1.5 to 2 equivalents.

The initial compounds of formula II, where X2is halogen, can be obtained from corresponding compounds of formula I, as shown in figure 3.

Scheme 3

where X2is a halogen, and L, R and k have the values listed previously.

Treatment of compounds of formula I halogenation reagent, usually in the presence of the solvent gives the corresponding halogenoalkane formula II. Halogenation reagents that can be used include oxychloride phosphorus, trihalogen phosphorus, pentachloride phosphorus, thionyl chloride, dialoginterface, dialoginterface, oxalicacid, phosgene, tetraploid and sulphur TRIFLUORIDE (diethylamino)sulfur. Suppose the equipment are oxychloride phosphorus and pentavalent phosphorus. To obtain a complete conversion, you need to use at least 0.33 equivalent oxychloride phosphorus in relation to the compound of formula I (i.e. the molar ratio of oxychloride phosphor of formula I is at least 0,33), preferably from about 0.33 to 1.2 equivalent. To obtain a complete conversion of at least 0.20 equivalent pentachloride phosphorus in relation to the compound of formula I, should be used, preferably, from about 0.20 to 1.0 equivalent. Typical solvents for the 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, diethyl ether and the like, and polar aprotic solvents such as acetonitrile, N,N-dimethylformamide and the like. May be added an organic base, such as triethylamine, pyridine, N,N-dimethylaniline or the like. Also a matter of choice is the addition of a catalyst, such as N,N-dimethylformamide. Preferred is a method in which the solvent is acetonitrile, and the base is missing. Usually when using solvent acetonitrile, neither the base nor the catalyst. Predpochtitel the process is carried out by mixing the compounds of formula I in acetonitrile. Then add halogenation reagent within a suitable time, and then the mixture is maintained at a desired temperature until, until the reaction is complete. The reaction temperature is usually between about 20°and a boiling point of acetonitrile, and the reaction time is about less than 2 hours. The reaction mass is then neutralized with inorganic base, such as sodium bicarbonate, sodium hydroxide, and the like, or an organic base, such as sodium acetate. The desired product, compound of formula II may be isolated by methods known in the art, including extraction, crystallization and distillation.

As shown in figure 4, the starting compounds of formula II, where R1is OS(O)mR1or OP(O)p(OR2)2can also be obtained from corresponding compounds of formula I by reacting with X3S(O)mR1(2) or X3R(O)p(OR2)2(3), respectively, where X3is a nucleophilic reaction of the deleted group. Halogen, such as Cl, especially suitable for X3. Also suitable for X3S(O)mR1is X3representing X3S(O)mR1(i.e. formula 2 represents R1S(O)mOS(O)mR1); X3representing OS(O) mR1especially suitable when R1is CF3. Because of the ease of synthesis and relatively low rates especially preferably, when X3is Cl.

Scheme 4

where X2is a OS(O)mR1or OP(O)p(OR2)2X3is the deleted group, and L, R, R1, k, m and p have the values listed previously.

With this method the compound of formula I result in interaction with the compound of the formula 2 (for X2which OS(O)mR1) or equation 3 (for X2which is the OP(OH)p(OR2)2), usually in the presence of a solvent and base. Suitable solvents include dichloromethane, tetrahydrofuran, acetonitrile and the like. Suitable bases include tertiary amines (e.g. triethylamine, N,N-diisopropylethylamine) and ionic bases such as potassium carbonate and the like. The tertiary amine is preferred as the base. Usually use at least one equivalent, preferably, a slight excess, e.g. 5-10%) of the compounds of formula 2 or formula 3 and the base relative to the compound of formula I to achieve full conversion. The reaction is usually carried out at a temperature between about -50°and the boiling point of the solvent, more than is usual between approximately 0° C and ambient temperature (i.e. approximately from 15 to 30°). The reaction is usually completed within a couple of hours to several days; the course of the reaction can be controlled by using such techniques, known to specialists as thin layer chromatography and analysis1H NMR spectrum. The reaction mixture is then treated so as washing with water, the osushivaniya the organic phase and evaporation of the solvent. The desired product, compound of formula II may be isolated by methods known in the art, including extraction, crystallization and distillation.

Because the formula IIa is a subspecies of the formula II, the compounds of formula IIa can be obtained from corresponding compounds of formula Ia, which is a subspecies of the formula I by the methods already described for schemes 3 and 4.

where R3, R4, Z and n have the meanings specified for formula IIa.

The compounds of formula I can be obtained by a large number of modern methods of synthesis known in the art. For example, the compounds of formula Ia can be obtained from compounds of formulas 4 and 5, as shown in scheme 5.

Scheme 5

where R3, R4, Z and n have the meanings specified for formula IIa.

In this method, hydrazine powered compound of formula 4 lead in aimogasta with the compound of the formula 5 (you can use fumaric ester or malaty ester) in the presence of base and solvent. The base is usually alkoxides metal salt, such as sodium methoxide, potassium methoxide, ethoxide sodium, atoxic potassium tert-piperonyl potassium tert-piperonyl lithium and the like. You need to use more than 0.5 equivalents of base relative to the compound of formula 4, preferably from 0.9 to 1.3 equivalents. You need to use more than 1.0 equivalent of compound of formula 5, preferably from 1.0 to 1.3 equivalent. You can use proton polar and polar aprotic solvents, such as alcohols, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide and the like. Preferred solvents are alcohols, such as methanol and ethanol. Particularly preferably, the alcohol was the same as in the preparation of fumaric and malatova esters and alkoxides Foundation. The reaction is usually carried out by mixing the compounds of formula 4 and the base in the solvent. The mixture can be heated or cooled to the desired temperature, and the compound of formula 5 may be added for some period of time. Usually the reaction temperature is between 0°and the boiling point of the used solvent. The reaction can be conducted at a pressure above atmospheric in order to increase the boiling point of the solvent. Typically, the preferred temperature is between about 3 and 90° C. While adding should be so short, as it allows heat dissipation. Typically, the time added is from 1 minute to 2 hours. The optimum reaction temperature and time add change depending on the characteristics of the compounds of formula 4 and formula 5. After the addition the reaction mixture was kept for some time at the reaction temperature. Depending on the reaction temperature required aging time can be from 0 to 2 hours. Normal aging time ranges from 10 to 60 minutes. The reaction mass may then be acidified by the addition of 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 of the functional group

-CO2R4the compounds of formula Ia can be hydrolyzed to CO2N, for example, the presence of water in the reaction mixture may cause such hydrolysis. If a carboxylic acid (-CO2N), it can be turned back in-CO2R4where R4is, for example, With1-C4the alkyl, using the methods of esterification are well known to the specialists. The desired product, a compound of formula Ia can be isolated by methods known in the art, such as crystallization, extra the licensing or distillation.

Believe that the person skilled in the art using the preceding description can apply this invention to its fullest extent. Therefore, the following examples should be construed as merely illustrative and not limiting the disclosure in any way. Stage the following examples illustrate the methodology for each stage in the overall transformation in the synthesis, and the source material for each stage may not necessarily be obtained by special preparative work, the methodology of which is described in other examples or stages. Percentages are by weight, except for mixtures of solvent for chromatography or where specified otherwise. Parts and percentages for mixtures of solvents for chromatography are presented in volume, unless otherwise indicated. Spectra1H NMR represented in ppm drop fields from tetramethylsilane; "s" means singlet, "d" means doublet, "t" means triplet, "cu" means Quartet, "m" means multiplet, "DD" means doublet of doublets, "dt" means doublet of triplets, and "Shir. with" means broad singlet.

EXAMPLE 1

Getting ethyl-3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate by replacing chlorine with bromine

Stage A: Getting ethyl-2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolecarboxylate

A 2-liter chetyrehosnuju to the forehead, equipped with a mechanical stirrer, thermometer, addition funnel, reflux condenser and input for nitrogen, download absolute ethanol (250 ml) and ethanolic solution of ethoxide sodium (21%, 190 ml, 0,504 mol). The mixture was heated to reflux distilled at about 83°C. it was Then treated with 3-chloro-2-(1H)-pyridinemethanol (68,0 g, 0,474 mol). The mixture was again heated to reflux distilled over a period of 5 minutes. Yellow thick mixture was then treated by adding dropwise, diethylmaleate (88,0 ml, 0,544 mol) over a period of 5 minutes. Speed reflux distilled significantly increased during the addition. By the end of adding all starting material had dissolved. The obtained orange-red solution was kept at reflux distilled within 10 minutes. After cooling to 65°the reaction mixture was treated with glacial acetic acid (50,0 ml, 0,873 mol). Formed precipitate. The mixture was diluted with water (650 ml), causing the precipitate to dissolve. The orange solution was cooled in an ice bath. The product began to precipitate at 28°C. the Thick slurry was kept at about 2°C for 2 hours. The product was isolated by filtration, washed with an aqueous solution of ethanol (40%, 3×50 ml) and then air-dried on the filter for about 1 hour. The product, compound named in the heading, received in the form of vysokobarotermicheskogo light orange powder (70,3 g, 55% yield)own destiny, no significant impurities were observed at 1H NMR.

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

Stage: Getting ethyl-3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate

A 2-liter chetyrehosnuju flask equipped with a mechanical stirrer, thermometer, reflux condenser and the input of nitrogen was loaded acetonitrile (1000 ml), ethyl-2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolecarboxylate (i.e. the product from step A) (91,0 g of 0.337 mol) and phosphorus oxychloride (35,0 ml, the 0.375 mol). By adding phosphorus oxychloride, the mixture spontaneously heated from 22 to 25°and the formed precipitate. Light yellow thick suspension was heated to reflux distilled at 83°during the period, equal to 35 minutes, after which the precipitate was dissolved. The obtained orange solution was kept at reflux distilled within 45 minutes, after which it became black and green. The reflux condenser was replaced with a distillation head and 650 ml of solvent was removed by distillation. The second 2-liter chetyrehosnuju flask equipped with a mechanical stirrer, was loaded sodium bicarbonate (130 g, 1.55 mol) and water (400 ml). Concentrated the reaction mixture was added to the thick suspension of sodium bicarbonate in 15 minutes. The obtained two-phase mixture was vigorously stirred for 20 minutes, at this time, the formation of gas has ceased. The mixture times alali dichloromethane (250 ml) and then was stirred for 50 minutes. The mixture was treated with telicom® (celite®) 545, diatomaceous earth, accelerator filter (11 g) and then filtered to remove a black resinous substance, which interfere with the separation of the phases. Since the filtrate was slowly divided into separate phases, it was diluted with dichloromethane (200 ml) and water (200 ml) and was again treated with telicom® 545 (15 g). The mixture was filtered and the filtrate was transferred into a separation column. The heavier dark green organic layer was separated. Coarse-grained layer (50 ml) was re-filtered and then added to the organic layer. The organic solution (800 ml) was treated with magnesium sulfate (30 g) and silica gel (12 g) and the thick suspension was stirred with a magnetic stirrer for 30 minutes. The thick suspension was filtered to remove the magnesium sulfate and silica gel, which was dark blue-green. Layer on the filter was washed with dichloromethane (100 ml). The filtrate was concentrated on a rotary evaporator. The product consisted of a dark amber oil (92.0 g, 93%). The only significant impurities observed1H NMR, were 1% of the initial substances and 0.7% acetonitrile.

1H NMR (DMSO-d6) δ: to 1.15 (t, 3H), 3,26 (DD, 1H), to 3.58 (DD, 1H), 4,11 (square, 2H), 5.25-inch (DD, 1H), 7,00 (DD, 1H), to 7.84 (d, 1H), 8,12 (d, 1H)

Stage C: Getting ethyl-3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate

Methyl hydrogen was passed through the RAS is a thief ethyl-3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (i.e. the the product from step C) (8,45 g of 29.3 mmol) in dichloromethane (85 ml). After 90 minutes the transmission of gas was stopped and the reaction mixture was washed with an aqueous solution of sodium bicarbonate (100 ml). The organic phase was dried and evaporated under reduced pressure to get the product named in the title, in the form of oil (9.7 g, 99% yield)which crystallized upon standing.

1H NMR (CDCl3) δ to 1.19 (t, 3H), 3,24 (1/2 of AB in the configuration of ABX, J=9,3, 17.3 Hz, 1H), 3,44 (1/2 of AB in the configuration of ABX, J=11,7, 17.3 Hz, 1H), 4,18 (square, 2H), 5.25 in (X of ABX, 1H, J=9,3, to 11.9 Hz), 6,85 (DD, J=4,7, 7.7 Hz, 1H), 7,65 (DD, J=1,6, 7,8 Hz, 1H), 8,07 (DD, J=1,6, 4.8 Hz, 1H)

EXAMPLE 2

Getting ethyl-3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate by replacing tosilata bromine

Stage A: Getting ethyl-1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-were)sulfonyl]oxy]-1H-pyrazole-5-carboxylate

The triethylamine (3.75 g, 37,1 mmol) was added dropwise to a mixture of ethyl-2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolecarboxylate (i.e. the product from example 1, stage A) (10.0 g, 37,1 mmol) and p-toluensulfonate (7,07 g, 37,1 mmol) in dichloromethane (100 ml) at 0°C. was Added an additional portion of the p-toluensulfonate (0.35 g, to 1.83 mmol) and triethylamine (0,19 g, 1.88 mmol). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The mixture then was diluted with dichloromethane (200 ml) and washed with water 3× 70 ml). The organic phase was dried and evaporated, and remained the product named in the title, in the form of oil (13,7 g, 87% yield), which was slowly formed crystals. The product, recrystallized from ethyl acetate/hexanol, melted at 99,5-100°C. IR (purified vaseline oil): 1740, 1638, 1576, 1446, 1343, 1296, 1228, 1191, 1178, 1084, 1027, 948, 969, 868, 845 cm-1.

1H NMR (CDCl3) δ to 1.19 (t, 3H), of 2.45 (s, 3H), 3,12 (1/2 of AB in the configuration of ABX, J=17,3, 9 Hz, 1H), 3.33 and (1/2 of AB in the configuration of ABX, J=17,5, and 11.8 Hz, 1H), 4,16 (square, 2H), 5,72 (X of ABX, J=9, 11.8 Hz, 1H), 6,79 (DD, J=4,6, and 7.7 Hz, 1H), was 7.36 (d, J=8,4 Hz, 2H), 7,56 (DD, J=1,6, 7,8 Hz, 1H), 7,95 (d, J=8,4 Hz, 2H), 8,01 (DD, J=1,4, 4.6 Hz, 1H)

Stage: Getting ethyl-3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate

Methyl hydrogen was passed through a solution of ethyl-1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-were)sulfonyl]oxy]-1H-pyrazole-5-carboxylate (i.e. the product from step A) (5 g, of 11.8 mmol) in dibromomethane (50 ml). After 60 minutes the transmission of gas was stopped and the reaction mixture was washed with an aqueous solution of sodium bicarbonate (50 ml). The organic phase was dried and evaporated under reduced pressure to get the product named in the title, in the form of oil (to 3.92 g, 100% yield)which crystallized upon standing. Range1H NMR of this product was the same as presented for the product from example 1, step C.

EXAMPLE 3

Poluchenie-3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate by replacing benzosulfimide bromine

Stage A: Obtain 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1H-pyrazole-5-carboxylate

The triethylamine (1.85 g, 18.5 mmol) dropwise over 1 hour was added to a mixture of ethyl-2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolecarboxylate (i.e. the product from example 1, stage A) (5.0 g, 18.5 mmol) and benzosulfimide (3,27 g, 18.5 mmol) in dichloromethane (20 ml) at 0°C. the Temperature was allowed to rise so that it exceeded 1°C. After stirring the reaction mixture additionally within 2 hours was added another portion of benzosulfimide (0.5 g, of 1.85 mmol). Then to the mixture was added dropwise another portion of triethylamine (0.187 g, of 1.85 mmol). After stirring for a further 0.5 hour, the mixture was distributed between water (100 ml) and dichloromethane (100 ml). The organic layer was dried (MgSO4) and evaporated to obtain the product named in the title, in the form of an orange solid (7,18 g, 94% yield). The product, recrystallized from ethyl acetate/hexanol, melted at 84-85°C.

IR (purified vaseline oil; nujol): 1737, 1639, 1576, 1448, 1385, 1346, 1302, 1233, 1211, 1188, 1176, 1088, 1032, 944, 910, 868, 846 cm-1.

1H NMR (CDCl3) δ: 1,19 (t, 3H), 3.15 in (1/2 of AB in the configuration of ABX, J=8,8, 17.3 Hz, 1H), 3,36 (1/2 of AB in the configuration ABX,J=11,8, 17.3 Hz, 1H), 4,17 (square, 2H), 5,23 (X of ABX, J=8,8, 11.8 Hz, 1H), 6,78 (DD, J=2,8, 4.8 Hz, 1H), 7,71-of 7.55 (m, 4H), 8,01 (DD, J=1,6, 4.6 Hz, 2H), 8,08 (DD, J=1,0, and 2.6 Hz, 2H)

Stage b: N is the receiving ethyl-3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate

A solution of 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1H-pyrazole-5-carboxylate (i.e. the product from step A) (1.0 g, 2,44 mmol) in acetic acid (4 ml) was added to a solution of hydrogen bromide in acetic acid (33%, 1.2 g, 4,89 mmol). After about 1 hour the reaction mixture was added to saturated aqueous solution of sodium bicarbonate (100 ml). The mixture was then extracted with ethyl acetate (2×50 ml) and the combined extracts were dried (MgSO4) and evaporated to obtain the product named in the title, in the form of oil (0,69 g, 85%), which slowly crystallized.1H NMR spectrum was similar to that presented for the product from example 1, step C.

Using the procedures described herein and methods known in the art, the compounds of formula II can be converted into compounds of formula I, as shown in relation to formulas Ia and IIa in table 1. The table uses the following abbreviations: t is tertiary, s is secondary, n is normal, i is ISO, Me represents methyl, Et is ethyl, Pr is propyl, i-Pr represents isopropyl, t-Bu is tertiary butyl, and Ph represents phenyl.

Method for the preparation of 3-halo-4,5-dihydro-1H-pyrazoles of this izopet the deposits can be used to obtain a number of compounds of formula I, which are suitable as intermediates for obtaining of means of crop protection, pharmaceuticals and other products of fine chemical technology. In the list of 3 lists examples of 3-halo-4,5-dihydro-1H-pyrazoles, which can be obtained by the method of this invention from the corresponding 4,5-dihydro-1H-pyrazoles with OS(O)mR1(for example, OS(O)2CH3or OS(O)2Ph), RR(OH)p(OR2)2(for example, OP(O)(OMe)2or different halogen substituent (for example, Cl, replacement, Br, or Br, Cl replacement), including a 3-halo-4,5-dihydro-1H-pyrazoles, which are suitable for receiving products that are used as fungicides, herbicides or for regulating plant growth. These examples should be considered illustrative, but not limiting, various applications of the method of the present invention. Other compounds which can be obtained by the method of the present invention may be suitable for the production of pharmaceutical products such as anti-inflammatory agents, means of a person's allergies, anticonvulsants, sedatives, etc.

List 3 examples of 3-halo-4,5-dihydro-1H-pyrazoles

Among the compounds obtained p the method of the present invention, especially suitable for producing compounds of formula III, the compounds of formula Ia

where Z, X1, R3and n are as defined above; R6is CH3, F, Cl or Br; R7represents F, Cl, Br, I or CF3; R8Ais1-C4alkyl; and R8brepresents N or CH3. Preferably, Z is N, n is 1, and R3is Cl or Br and is in the 3rd position.

The compounds of formula III are useful as insecticides, which are described, for example, in PCT publication no WO 01/70671, published on 27 September 2001, and also in patent application U.S. 60/324173 registered on September 21, 2001, the patent application U.S. 60/323941 registered on September 21, 2001, and patent application U.S. 60/369661, registered on April 2, 2002, Obtaining compounds of formula 8 and formula III is described in patent application U.S. 60/400352 registered on July 31, 2002 [VA US PRV], and patent application U.S. 60/446438, registered on February 11, 2003 [VA US PRV1], and is included here in its entirety by reference; and in the patent application U.S. 60/369660, registered on April 2, 2002

The compounds of formula III can be obtained from corresponding compounds of formula Ia by the methods described in schemes 6-9.

As shown in scheme 6, the compound of formula Ia is treated with an oxidizing medium spans the PTO, it is possible in the presence of acid.

Scheme 6

where R3, R4, Z, X1and n are as previously defined for formula Ia.

The compound of formula Ia, where R4is1-C4alkyl is preferred as the source materials for this stage. The oxidizing agent may be hydrogen peroxide, organic peroxides, potassium persulfate, sodium persulfate, ammonium persulfate, monopersulfate potassium (e.g., Oxone®) or potassium permanganate. To obtain a complete conversion, you need to use at least one equivalent of oxidizing substances in relation to the compound of formula Ia, preferably from about one equivalent to two equivalents. This oxidation is usually carried out in the presence of a solvent. The solvent can be an ether, such as tetrahydrofuran, p-dioxane and the like, complex organic ester, 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 keys, the PTA and the like. This acid, when it is used, it is necessary to use more than 0.1 equivalents relative to the compound of formula Ia. In order to achieve full conversion, you can use from one to five equivalents of acid. For compounds of formula Ia where Z is CR5preferred oxidizing agent is hydrogen peroxide and the oxidation is preferably carried out in the absence of acid. For compounds of formula Ia where Z is N, the preferred oxidizing agent is potassium persulfate, and the oxidation is preferably conducted in the presence of sulfuric acid. The reaction can be conducted by mixing the compounds of formula Ia in the desired solvent and, if applicable, of the acid. You can then add the oxidizing agent at a suitable speed. The reaction temperature usually ranges from as low as about 0°C, the boiling point of the solvent to obtain a rational reaction time until completion of the reaction, preferably, less than 8 hours. The desired product, compound of formula 6 may be selected by methods known in the art, including extraction, chromatography, crystallization and distillation.

Connection carboxylic acid of formula 6, where R4is H, can be obtained by hydrolysis of the corresponding ester compounds of formula 6, where, for example, R4 is1-C4the alkyl. Carboxyl ester compounds can be converted into compounds, carboxylic acids, many methods, including nucleophilic cleavage in anhydrous conditions or hydrolytic methods, including the use or acids or bases (see T.W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nded., John Wiley & Sons, Inc., New York, 1991, pp. 224-269, in the review of methods). With regard to compounds of formula 6, the preferred methods of hydrolysis, catalyzed by base. Suitable bases include alkali metal hydroxides (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 ester its shades of obtaining sodium or potassium salt of carboxylic acid. Acidification with a strong acid, such as hydrochloric acid or sulfuric acid, yields the carboxylic acid of formula 6, where R4is N. The carboxylic acid may be selected methods known in the art, including extraction, distillation and crystallization.

Connection pyrazolylborate acid of formula 6, where R4is H, with an Anthranilic acid of formula 7 gives benzoxazine formula 8. In figure 7 benzoxazine formula 8 is obtained directly by the follower of the CSOs add methanesulfonanilide in the presence of a tertiary amine, such as triethylamine or pyridine, to pyrazolylborate acid of formula 6, where R4is H, followed by the addition of Anthranilic acid of formula 7, followed by a second addition of tertiary amine and methanesulfonanilide.

where R3, R6, R7X1, Z and n have the meanings as defined above for formula III.

This technique usually produces a good yield of benzoxazinone. Obtaining of compound 8 from compound 6 described in example 3 step E of document US 2004/0198984 A1, 07.10.2004.

Figure 8 describes the alternative receiving benzoxazinones formula 8, including the connection of the acid chloride pyrazol acid of formula 10 with sativum anhydride of formula 9 with getting directly benzoxazinone formula 8.

where R3, R6, R7X1, Z and n have the meanings as defined above for formula III.

For this reaction a suitable solvent, such as pyridine or pyridine/acetonitrile. The anhydrides of the acids of formula 10 can be obtained from the corresponding acids of formula 6, where R4represents H, known methods, such as chlorination with thionyl chloride or oxalylamino.

An example of an alternative receiving benzoxazinones formula 8 below in example 4.

The compounds of formula III can be floor is obtained by the reaction benzoxazinones formula 8 with C 1-C4bonds alkylamines and (C1-C4alkyl)(methyl)amines of the formula II, as described in scheme 9.

where R3, R6, R7, R8a, R8bX1, Z and n have the meanings as previously defined.

The reaction may be carried out neat or in a number of suitable solvents, including acetonitrile, tetrahydrofuran, diethyl ether, dichloromethane or chloroform, at the optimal temperature in the range from room temperature to the temperature of reflux distilled solvent. The overall reaction benzoxazinones with amines to obtain anthranilamide well known from the chemical literature.

Obtain compound III from compound 8 described in example 3, stage F document US 2004/0198984 A1, 07.10.2004.

EXAMPLE 4

Getting 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-C,5-dichlorbenzene acid (104 g, 500 mmol) in dry dioxane under stirring at room temperature dropwise added trichlorethylene ether of Harborview acid (70 g, 350 mmol). The reaction mixture is slowly warmed up to 30°and the solid particles are almost completely dissolved before the formation of a thick suspension. Then the suspension was stirred at ambient temperature overnight, obtained the compound was filtered, washed with ethyl ether and received 82 g of white particles.

1H NMR (DMSO-d6) δ 7.88 (d, 1H), 8.07 (d, 1H), 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 (118 g, 390 mmol) in dichloromethane (1 l) was added N/N-dimethylformamide (8 drops). Oxalyl chloride was added dropwise for 1.5 hours. The resulting solution was stirred at room temperature overnight and then concentrated in vacuum. The selected acid chloride was dissolved in dry acetonitrile (200 ml) and added with stirring to a suspension of 6,8-dichloro-2H-3,1-benzoxazin-2,4(1H)-dione (the product of stage 1) (82 g, 350 mmol) in dry acetonitrile (200 ml). Added pyridine (175 ml) and the solution was heated for 4 hours with a capacitor. After cooled using an ice bath, allocated 152 g of white particles.

1H NMR (COCl3) δ 7.27 (d, 1H), 7.38 (t, 1H), 7.72 (s, 1H), 7.9 (d, 1H), 8.05 (s, 1H), 8.55 (d, 1H)

In respect of the review on chemistry benzoxazinones see Jakobsen et al., Biorganic and Medicinal chemistry 2000, 8, 2095-2103 and sources cited therein. See also Coppola, J. Heterocyclic Chemistry 1999, 36, 563-588.

1. Method for the preparation of 3-halo-4,5-dihydro-1H-pyrazol the compounds of formula Ia

where R3independently represents C1-C4alkyl, C2 -C4alkenyl,2-C4quinil,3-C6cycloalkyl,1-C4halogenated,2-C4halogenoalkanes,2-C4halogenoalkanes,3-C6halogenosilanes, halogen, CN, NO2With1-C4alkoxy, C1-C4halogenoalkane,1-C4alkylthio,1-C4alkylsulfonyl,1-C4alkylsulfonyl, C1-C4alkylamino,2-C8dialkylamino,3-C6cyclooctylamino, (C1-C4alkyl)(C3-C6cycloalkyl)amino, C2-C4alkylsulphonyl,2-C6alkoxycarbonyl,2-C6alkylaminocarbonyl,3-C8dialkylaminoalkyl or3-C6trialkylsilyl;

R4represents N or C1-C4alkyl;

Z is N or CR5;

R5represents N or R3;

n is an integer from 0 to 3

X1is halogen,

wherein the 4,5-dihydro-1H-pyrazole of the formula IIa

where X2is OS(O)mR1OP(O)p(OR2)2or halogen other than X1;

m is 1 or 2;

p is 0 or 1;

R1selected from alkyl, halogenoalkane and phenyl, possibly substituted by the CSO from 1 to 3 substituents, selected from alkyl and halogen; and

each R2independently selected from alkyl, halogenoalkane and phenyl, possibly substituted from 1 to 3 substituents selected from alkyl and halogen;

R4, Z, R5and n have the above meanings;

subjected to interaction with the compound of the formula HX1in the presence of a suitable solvent.

2. The method according to claim 1, in which m is 2 and p is 1.

3. The method according to claim 2, in which X2is halogen or OS(O)mR1.

4. The method according to claim 3, in which X2is Cl or OS(O)mR1and R1is C1-C2the alkyl, phenyl or 4-were.

5. The method according to claim 1, wherein X1is Cl or Br.

6. The method according to claim 6, in which R4is C1-C4the alkyl.

7. The method according to claim 6, in which Z is N, n is 1, and R3is Cl or Br and a is a 3-position.

8. The method according to claim 6, in which X1is Br, X2is Cl or OS(O)mR1, m is 2 and R1is phenyl or 4-were.

9. The method of obtaining the compounds of formula III

where X1is halogen,

each R3independently represents C1-C4alkyl, C2-C4alkenyl,2-C4quinil,3-C6cycloalkyl,1 -C4halogenated,2-C4halogenoalkanes,2-C4halogenoalkanes,3-C6halogenosilanes, halogen, CN, NO2With1-C4alkoxy, C1-C4halogenoalkane,1-C4alkylthio,1-C4alkylsulfonyl,1-C4alkylsulfonyl, C1-C4alkylamino,2-C8dialkylamino,3-C6cyclooctylamino, (C1-C4alkyl)(C3-C6cycloalkyl)amino, C2-C4alkylsulphonyl,2-C6alkoxycarbonyl,2-C6alkylaminocarbonyl,3-C8dialkylaminoalkyl or3-C6trialkylsilyl;

Z is N or CR5;

R5represents N or R3;

R6is CH3, F, Cl or Br;

R7represents F, Cl, Br, I or CF3;

R8ais1-C4alkyl;

R8brepresents N or CH3; and

n is an integer from 0 to 3

with the use of the compounds of formula Ia obtained according to the method according to claim 1,

where R4is N or C1-C4the alkyl, including stage

(1) obtaining the compounds of formula 6, where R4is N

a) processing the oxidizing agent the compounds of the formula Ia with obtaining the compounds of formula 6:

(b) if R4in the compound of formula 6 obtained in stage a), is1-C4the alkyl, the compound of formula 6 obtained in stage a), is subjected to hydrolysis;

(2) obtaining the compounds of formula 8:

or

(C) the interaction of the above compounds of formula 6, where R4is H, obtained in stage (1), with the compound of formula 7:

or

(d1) the chlorination of the above compounds of formula 6, where R4is H, obtained in stage (1), with the formation of compounds of formula 10

and

(d2) the interaction of the above compounds of formula 10 with a compound of formula 9

and

(3) the interaction of the above compounds of formula 8 is obtained

at stage (2), with the compound of formula 11

10. The method according to claim 9, in which R4in the compound of formula Ia is C1-C4the alkyl.

11. The method according to claim 10, in which Z is N, n is 1, and R3is Cl or Br and a is a 3-position.

12. The method according to claim 10, in which X1is Br, X2is Cl or OS(O)mR1is 2, and R1is phenyl or 4-were.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention pertains to new 2,4-substituted indole with formula: I, its pharmaceutically accepted salt, where R1 represents phenyl, optionally substituted with one or two substitutes, chosen from a group, consisting of a halogen, C1-12alkyl, halogen C1-12alkyl, or represents thienyl; R2 represents residue of a saturated ring, consisting of six ring atoms, one or two of which are nitrogen atoms, and the others are carbon atoms, optionally substituted with one or two C1-12alkyls; R represents H, C1-12alkyl; R4 represents H; p represents 1 or 2; n represents 0,1 or 2. The compounds have antagonistic activity to the "5-ГТ6" receptor, which allows to use in pharmaceutical mixtures.

EFFECT: use in pharmaceutical mixtures.

10 cl, 7 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: here, described are new derivatives of 1H-1,2,4-triazole-3-carbozamide of the general formula (I) , wherein R is phenyl, possibly replaced by 1-2 halogen atoms, R1 is phenyl possibly replaced by 1-2 halogen atoms or trifluotomethyl group, or pyridile radical; R2 represents a hydrogen atom; R3 - C1-6-alkyl, C2-8-alcoxy, C3-8-cycloalkyl, possibly replaced with C1-3-zalkyl or ethynil, C2-8-bicycloalkyl, C4-8-alkenil, C3-8-trifluoroalkyl or C2-8-fluoroalkyl group or C3-8-cycloalkyl, group NR4R5, where R4 and R5 together with nitrogen atom to which they are coupled, form a monocyclic or bicyclic heterocyclic fragment with 5-8 ring atoms, the heterocyclic group of the above fragment contains one or two heteroatoms, selected from the group N and O, possibly replaced with C1-3-alkyl or R2 and R3 together with nitrogen atom to which they are coupled form 1,4'-bipyperidine radical, their pharmaceutically acceptable salts.

EFFECT: pharmaceutical composition is used for treatment of disturbances involving neurotransmission of cannabinoids.

5 cl, 43 ex, 1 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention can be used in medicine and pharmaceutical industry and relates to the cell proliferation inhibitor and to the anti-tumor agent, which contains the 3-phenylcinnolin analogue as an active component, and has the formulas , where J presents the A-C-B, where C is carbon, A is alcoxy, OH, acyloxy or amino acid residue, B is hydrogen, alkyl group, carbonyl group or = N-NH2 together with A, K - (CH2)q; L - N-W, where N -nitrogen atom, or W-C-W′, where C - carbon atom; W - alkyl group or hydrogen atom; W′ - alkyl, phenyl, carboxyl or alcoxycarbonyl group or hydrogen; J-K-L-M corresponds to C(O-Y)=CH-C(W)=CH or M - group (CH2)m; Z - oxygen; X - alcoxyl group, halogenated alkyl group, nitrogroup, cyanogroup or halogen; X' - halogen or hydrogen; m and q = 1, n and n' = 0 or 1, and (n + n') less than 2.

EFFECT: improved anti-tumor agent is available based on described compound.

82 ex

FIELD: chemistry.

SUBSTANCE: invention relates to crystallic hydrate of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one of example В1, to method for preparation thereof, to anhydrous crystalline forms of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one of examples D1, С1, Е1, as well as to pharmaceutical composition. Technical effect - easy commercial preparation of 3-(2-cyanophenyl)-5-(2-pyridyl-1-phenyl-1,2-dihydropyridine-2-one as a homogeneous crystalline form, which is an АМРА receptor antagonist and/or kainate receptor inhibitor.

EFFECT: facilitation of dyhydropyridine preparation.

26 cl, 9 ex, 11 tbl

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

SUBSTANCE: invention relates to novel substituted esters of 1H-indol-3-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutical acceptable salts and/or hydrates. Compounds can be used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza. In compound of the general formula (1) R1, R41 and R42 each represents independently of one another a substitute of amino group chosen from hydrogen atom, optionally linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 carbon atom in ring with one or some heteroatoms chosen from nitrogen oxygen or sulfur atoms; or R41 and R42 in common with nitrogen atom to which they are bound form 5-10-membered azaheterocycle or guanidyl through R41 and R42; R2 represents an alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and possibly an annelated heterocycle that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention.

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

22 cl, 3 tbl, 8 dwg, 6 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidone of the formula (I): wherein Q means =N, =C(R24)-; X-Y means -CH2-CH2-, -CH=CH-, -CH2-O-; R1, R1.1 and R1.2 are chosen independently from group comprising hydrogen atom (H), halogen atom, halogen-(C1-C6)-alkyl, -CN, (C1-C6)-alkoxy group; R21, R22 and R23 are chosen independently of one another from group comprising H, halogen atom; R24 means H; R3 means -NHR6; R4 means H; R6 means -C(O)H, -C(O)-(C1-C3)-alkyl, -C(O)-halogen-(C1-C3)-alkyl, -C(O)O-(C1-C3)-alkyl, -C(O)-NH2, -SO2-(C1-C3)-alkyl, and also its individual isomers, racemic and nonracemic mixtures. Proposed compounds inhibit activity of monoamine oxidase B that allows its using in prophylaxis and treatment of disease mediated by monoamine oxidase B inhibitor, in particular, Alzheimer's disease and senile feeble-mindedness.

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

15 cl, 4 sch, 31 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention relates to synthesis of biologically active derivatives of pyridylisoquinolines. Invention describes 2,2-dimethyl-4-(4,6-dimethyl-2-pyridon-3-yl)-1,2-dihydrobenzo[f]isoquinoline hydrochloride of the formula: that elicits the direct anticoagulant effect. Invention provides preparing a novel compound possessing useful biological properties.

EFFECT: valuable biological property of compound.

1 tbl

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means -lower alkyl, -CH2-aryl, -cycloalkyl, -(CH2)3, -OC(=O)CH3, -lower alcohol, -lower alkyl-R10, -CH2COOH or -CH2CH2OCH2CH3; R2 means -lower alkyl, -CH2-aryl, -lower alcohol, -CH2C(=O)-NH2 or lower alkyl-R10 wherein at least one radical among R1 or R2 means -CH3; R3 means -COOH, -lower alkyl-COOH, -lower alcohol, -CH2OCH2, -CH2NH2, -CHNHSO2R11, -C(=O)-R12, -(CH2)nNHC(=O)-R13, -(CH2)mC(=O)N-(R15)(R16), -C(=NH)-R17 or -(CH2)n-R18; R4 means hydrogen atom (-H), -lower alkoxy group, -O-C(R7R8)C(=O)-R19, -halogen atom, -SCH3, -C=CHC(=O)-R10, -CH2CH2C(=O)-R10, -O-lower alcohol, -OCH2CH(OH)CH2N=N±N-, -OCH2CH2OCH2CH2Cl, -NHC9=O)-CH2-lower alkyl, -O(CH2)n-cycloalkyl, -O-lower alkene or 5-membered unsaturated heterocyclic ring comprising one heteroatom representing sulfur (S) or oxygen (O) atom; R5 and R6 mean independently -H, -halogen atom or -lower alkoxy group; R7 and R8 mean independently -H or -CH3; R10 means 5-6-membered saturated heterocyclyl comprising 1 or 2 heteroatoms, such as N and O, and this group is bound with other moiety of molecule by a ring N atom; R11 means -CF3, -lower alkyl, -CH2Cl, -CH2CF3 or -R12; R12 means 5-6-membered saturated substituted or unsubstituted heterocyclic ring comprising 1 heteroatom, such as N, O and S wherein substituted ring represents heterocyclic ring substituted with -OH or -phenyl; R13 means -lower alkyl, -lower alkoxy group or -(CH2)nR14; R14 means 5-6-membered saturated or unsaturated heterocyclic ring comprising 1 and 2 heteroatoms, that are chosen from group comprising N and O; R15 means -H, -lower alkyl, -OH, -lower alkoxy group or -CH2COOCH2CH3; R17 means -lower alkoxy group, -NH2 or -N-lower alkyl; R18 means saturated or unsaturated 5-membered substituted or unsubstituted heterocyclic ring comprising from 1 to 4 heteroatoms, such as N, O and S wherein substituted ring represents heterocyclic ring that is substituted by one or two cyclic carbon atoms by =O, or it is substituted by cyclic N atom by -lower alcohol or -lower alkyl; R19 means -OH, -NHCH(CH3)2, -N(CH3)CH2-aryl, -N(CH3)-lower alkyl, 1-(aryl-(CH2)n-)-[1,4]-diazin-4-yl or 5-6-membered saturated heterocyclyl and optionally substituted with lower alkyl comprising 1 or 2 heteroatoms, such as N and O; m = 0, 1 or 2; n = 0 or 1, and their pharmaceutically acceptable salts and esters. Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to GFAT and containing the effective amount of compound of the formula (I). Invention provides expanding assortment of agents possessing inhibitory activity with respect to GFAT. Proposed compounds can be used as inhibitors of GFAT, and pharmaceutical composition possessing inhibitory activity with respect to GFAT containing above said compound of the formula (I) also.

EFFECT: valuable biochemical properties of compounds and pharmaceutical composition.

25 cl, 134 ex

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

FIELD: chemistry.

SUBSTANCE: the said invention relates to о-cyclopropylcarboxanilides of general formula (I) , where Het stands for pyrrolyl, pyrazolyl or thiazolyl, each being substituted with R4, R5 and R6 groups; R1, RЗ stand for hydrogen or halogen; R3 stands for С2-12 alkyl, С3-12 cycloalkyl, С3-12 cycloalkyl substituted with С1-3 alkyl, phenyl or halogen-substituted phenyl; and R4, R5 and R6 are independently selected from hydrogen, halogen, С1-4 alkyl or С1-4 haloalkyl, provided that at least one of R4, R5 and R6 is other than hydrogen. Intermediates used in synthesis of I, as well as antimicrobial composition and methods for control and prevention of cultivated plants' infection with phytopathogenic microorganisms are described.

EFFECT: compounds can be used to protect plants from being infected with phytopathogenic microorganisms.

8 cl, 7 tbl, 12 ex

FIELD: organic chemistry, fungicides.

SUBSTANCE: invention describes pyrazolylcarboxanilides of the formula (I) wherein R means difluoromethyl or trifluoromethyl group; R1 and R2 mean independently of one another halogen atom or (C1-C6)-alkyl; R3 means fluorine atom, and agent and method for control of undesirable fungi using compounds of the formula (I), and novel intermediate substances - derivatives of aniline and halogenpyrazolcarboxanilides. Compounds of the formula (I) elicit fungicide properties and can be used in protection of plants.

EFFECT: valuable properties of compounds and agent.

15 cl, 8 tbl, 10 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention relates to compounds of the formula (1) , their N-oxides and salts that can be used in agriculture wherein values A, B, J, R1, R3, R4 and n are given in the invention claim. Also, invention describes a method for control of arthropoda pests to provides high productivity that comprises applying the effective dose of compound of the formula (1) on arthropoda pests and in medium of their habitation, and a the composition with arthropocide activity comprising compounds of the formula (1).

EFFECT: valuable properties of compounds and composition.

23 cl, 34 tbl, 759 ex

FIELD: organic chemistry, agriculture, insecticides.

SUBSTANCE: invention relates to a substituted anilide derivative of the formula (I): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2; Z represents oxygen atom; Q means a substitute represented by any of the following formulae: Q1-Q3, Q6, Q8-Q12, Q14-Q19, Q21 and Q23 (wherein each among Y1 that can be similar or different represents halogen atom, (C1-C6)-alkyl group, and so on); Y2 represents (C1-C6)-alkyl group or halogen-(C1-C6)-alkyl group; Y3 represents (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl group or substituted phenyl group; p represents a whole number from 1 to 2; q represents a whole number from 0 or 2; r represents a whole number from 0 to 2. Also, invention proposes a chemical for control of pests of agricultural and fruit crops. The chemical comprises substituted anilide derivative of the formula (I) as an active component and represents insecticide, fungicide or acaricide. Also, invention proposes a method for addition of the chemical for control of pests of agricultural and fruits crops. Also, invention proposes aniline derivative represented by the general formula (II): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2. Invention provides the development of anilide derivative as insecticide, fungicide and acaricide against pests of agricultural and fruit crops.

EFFECT: valuable properties of compound.

5 cl, 6 tbl, 27 ex

FIELD: organic chemistry, fungicides, agriculture.

SUBSTANCE: invention describes pyrazolcarboxamide of the formula (I) wherein if X means oxygen atom (O) then R1 represents (C1-C3)-alkoxy-(C1-C3)-alkyl; R2 means (C1-C3)-halogenalkyl; R3 means fluorine (F), chlorine (Cl) or bromine atom (Br), and if X means sulfur atom (S) then R1 means (C1-C3)-alkyl; R2 means (C1-C3)-halogenalkyl; R3 means halogen atom. Also, invention describes a method for preparing compounds of the formula (I), a composition for control of microorganisms and prevention for their attack and damage of plants, and a method for control of phytopathogen organisms, and compound of the formula (V) wherein X means sulfur atom (S); R1 means (C1-C3)-alkyl; R2 means (C1-C3)-halogenalkyl; R3 means chlorine, bromide or iodine atom. Invention provides control and prevention in infection of plants with phytopathogenic microorganisms - fungi in agriculture and horticulture.

EFFECT: valuable agricultural properties of compounds.

9 cl, 4 tbl, 12 ex

The invention relates to N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-aripirazole-3-carboxamide, its pharmaceutically acceptable salt and solvate, which are strong antagonists of cannabinoid ST1receptors

The invention relates to substituted 1-phenylpyrazol-3-carboxamide formula (Ia) in which R1xis in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen; NRaRbdenotes a group selected from (a), (b), (C); R5and R6denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8)-alkenyl or R5and R6together with the nitrogen atom to which they are linked, represent a heterocycle selected from pyrrolidine, piperidine, research, piperazine, substituted in position 4 by Deputy R9; R7denotes hydrogen, (C1-C4)-alkyl or benzyl; R8denotes hydrogen, (C1-C4)-alkyl, or R7and R8together with the carbon atom to which they are attached, form a (C3-C5-cycloalkyl; R9denotes hydrogen, (C1-C4)-alkyl, benzyl or a group-X-NR'5R'6in which R'5and R'6represent, independently from each other, (C1-C6)-alkyl; R10denotes hydrogen, (C1-C4)-alkyl; s= 0-3; t=0-3, provided that (s+t) in the same group greater than or equal to 1; the divalent radicals a and E together with the atom is which in addition, may be substituted by one or more (C1-C4-alkilani; R2xand R3xdenote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cyclooctylmethyl provided that R2xand R3xdo not simultaneously denote hydrogen or R2xand R3xtogether form tetramethylene group; and their pharmaceutically acceptable salts

The invention relates to new compounds for combating pests, in particular derivatives carbanilide and fungicide-insecticidal tool based on them

The invention relates to pyrazole derivative of the formula I, where1means the group - NRR1R2or group-OR2, g2- g6the same or different and independently of one another denote hydrogen, halogen, C1-4alkyl, C1-4alkoxyl, trifluoromethyl, or C1-4allylthiourea; w2-w6the same or different and independently of one another denote hydrogen, halogen, C1-4alkyl, C1-4alkoxy or trifluoromethyl, provided that at least one of the substituents g2-g6and one of the substituents w2-w6different from hydrogen; R1means hydrogen or C1-4alkyl; R2- nah3-15-carbocyclic radical, unsubstituted or mono - or multiply substituted WITH1-4by alkyl; R3is hydrogen or the group CH2-R6; R4and R5each independently of one another denote hydrogen or C1-4alkyl; or R4means hydrogen and R5and w6together form an ethylene radical; R6means hydrogen, or when the deputies of the g2g3, g4, g5and/or g6different from1-4of alkyl, R6means hydrogen, C1-4alkyl or C1-5alkoxyl, and their salts

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

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