Conversion of 2-pyrazolines to pyrazoles using bromine

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula 1a, where X denotes a halogen or C1-C4halogenalkyl; Z denotes N or CR9; each R5 independently denotes halogen or C1-C4halogenalkyl; R9 denotes H, halogen or C1-C4halogenalkyl; R10 denotes H or C1-C4alkyl; and n is an integer from 0 to 3, involving bringing 2-pyrazoline of formula 2a, where X, Z, R5, R9, R10 and n assume values given above, into contact with bromine in a medium of a suitable inert organic solvent at temperature 80-180°C.

EFFECT: obtaining pyrazoles of formula 1a with high output and purity.

7 cl, 2 tbl, 3 ex

 

The scope of the invention

The invention relates to the conversion of 4,5-dihydro-1H-pyrazoles (also known as 2-pyrazoline) in the corresponding pyrazoles.

The level of technology

Patent PCT publication WO 03/016283 discloses a method of obtaining pyrazoles of the formula i

where R1represents halogen, R2represents, among others, With1-C4alkyl, C1-C4halogenated, halogen, CN, C1-C4alkoxy or1-C4halogenoalkane; R3is1-C4alkyl; X is N or CR4; R4represents N or R2; and n is from 0 to 3, provided that when X is CH then n is at least 1, which are used as intermediates for obtaining insecticides. The method involves processing the corresponding 2-pyrazoles of the formula ii oxidizer, optionally in the presence of acid.

When X represents CR2preferred oxidizing agent is hydrogen peroxide, and when X is N, the preferred oxidizing agent is potassium persulfate. However, continues to exist a need for new methods that would be less costly, more efficient, more flexible or easier to handle.

The essence of the image is etenia

The invention relates to a method for obtaining compounds of formula 1

where

X represents H, halogen, OR3or optionally substituted carbon group,

L represents an optionally substituted carbon group,

R1represents H or optionally substituted carbon group,

R2represents H, optionally substituted carbon group, NO2or SO2R4,

R3represents H or optionally substituted carbon group, and

R4represents an optionally substituted carbon group,

comprising contacting 2-pyrazoline formula 2

with bromine at a temperature of at least about 80°C.

The invention relates also to a method for obtaining compounds of formula 3

where

Z is N or CR9,

each R5independently represents halogen or1-C4halogenated,

R6is CH3, F, Cl or Br and

R7represents F, Cl, Br, I, CN or CF3,

R8ais1-With4alkyl,

R8brepresents N or CH3,

R9represents H, halogen or1-C4halogenated, and

n represents an integer from 0 to 3,

with the use the of the compounds of formula 1A

where R10represents H or optionally substituted carbon group, which is characterized by obtaining the compounds of formula 1A (i.e subspecies formula 1) in a manner that disclosed above.

Detailed description of the invention

Used herein, the terms "includes", "include", "includes", "including", "has", "having" or any other of their variation are intended to cover non-exclusive inclusion. For example, composition, process, method, object or device that contains a list of elements is not necessarily limited to only these elements but may include other elements not expressly listed or inherent to such a composition, process, method, object or machine. Further, unless specifically stated in the reverse sense, "or" inclusive or, not and exclusive or. For example, a condition a or b is satisfied by one of the following: a is true (or present) and b is false (or not present), a is false (or not present) and b is true (or present), and a and b are true (or present).

Also, the indefinite articles "a" and "an" before an element or component of the invention should not be construed as restrictive in terms of the number of individual cases (i.e. cases) cell battery (included) is the component. So "a" or "an" should be understood as including one or at least one, and verbal singular element or component also includes the plural unless it is obvious that the number must be unique.

When used in this description, the term "carbon group" refers to a radical in which the carbon atom attached to the remainder of formula 1 and 2. When the carbon group L, R1, R2, R3, R4, R10and X substituents are separated from the reactive center, they can cover a wide variety of groups on the basis of carbon, obtained by modern methods of synthetic organic chemistry. The method according to the invention is generally applicable for a wide range of source compounds of formula 2 and formula 1. Generally, it is preferable that the carbon group were not sensitive to the bromine in the reaction conditions. However, this invention is particularly suitable for the conversion of compounds of formula 2, having a carbon group, which are sensitive to the bromine in the other reaction conditions (e.g., at temperatures below 80°C). "Carbon group", therefore, includes alkyl, alkenyl and quinil, which may be straight or branched chain. "Carbon group" includes carbocyclic and heterocyclic to LCA, which may be saturated, partially saturated or fully unsaturated. Moreover, the unsaturated rings may be aromatic, if you meet the rule of Jokela. Carbocyclic and heterocyclic rings carbon group may form a polycyclic ring system containing multiple rings connected together. The term "carbocyclic ring" means a ring, in which the atoms forming the main ring of carbon atoms. The term "heterocyclic ring" means a ring, in which at least one of the main atoms of the ring is other than carbon. "Saturated carbocyclic" refers to a ring having a basis consisting of carbon atoms linked together by single bonds; unless otherwise specified, the remaining carbon valences 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. 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, when n is 0 or a positive number, associated with the ring rule X is Kehl. The term "aromatic carbocyclic ring system" includes fully aromatic carbocycle and carbocycle, in which at least one ring of a 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 unsaturated heterocycles in which any one of the rings in the ring system is not aromatic. The term "aryl" means a carbocyclic or heterocyclic ring or ring system in which at least one ring is aromatic, and the aromatic ring provides the connection to the rest of the molecule.

The carbon group specified for L, R1, R2, R3, R4, R10and X are optionally substituted. The terminology is "optionally substituted" in connection with the above carbon groups refers to carbon groups which are unsubstituted or have at least one non-hydrogen Deputy. Examples of 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, allmenareliars, alkoxycarbonyl, alkanolammonium, alkyloxycarboxylic, aryloxypropanolamine, each of which optionally additionally substituted, and halogen, cyano and nitro. Optional additional substituents independently selected from groups such as those given as examples of substituents to obtain additional groups of substituents for L, R1, R2, R3, R4, R10and X, such as halogenated, halogenoalkanes, halogenoalkane. As an additional example, alkylamino which may be optionally substituted by alkyl with the formation of dialkylamino. The substituents may be linked together, figuratively removing one or two hydrogen atoms from each of the two substituents or a substituent, and a basic molecular structure and connection of the radicals with the formation of cyclic or polycyclic structures, condensed or related to molecular structure, bearing substituents. For example, linking together adjacent hydroxy and methoxypropyl attached to the phenyl ring, gives a condensed structure dioxolane containing a bridging group,- O-CH2-O-. Linking together hydroxy-group and molecular structure to which it is attached, can give cyclic ethers, including epoxides. Examples of the substituents include oxygen, which when joined to the carbon forms a carbonyl functional group. Similarly, sulfur when joining the carbon forms a thiocarbonyl functional group. When the group 4,5-dihydropyrazolo formula 2 is the one ring, tying together R1and R2or L and R2will result in a condensed bicyclic or polycyclic ring system.

As mentioned herein, "alkyl", used either alone or in compound words such as "alkylthio" or "halogenated"includes straight or branched and the keel, 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 positions available for Deputy may be busy alkilani, which are selected independently. "Alkenyl" includes straight or branched alkenes, 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 straight or branched alkynes such as ethinyl, 1-PROPYNYL, 2-PROPYNYL and the different isomers of butenyl, pentenyl and hexenyl. "Quinil" includes 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 straight or branched chain. Examples of "alkenylacyl" include N2C=SNSN2Oh, (CH3)2C=SNSN2Oh, (CH3)SN=SNSN2Oh, (CH3)CH=C(CH3)CH2Oh and CH2=SNSN2CH2O. "Alkyloxy" includes alkyloxy straight or branched chain. Examples of "alkyloxy include NA≡CLO2O, CH3With≡CLO2And (CH3)≡CLO2CH2O. Alkylthio includes ancilliary with direct is Oh or branched chain, such as methylthio, ethylthio and various isomers of property, butylthio, pentylthio and hexylthio. "Alkylsulfonyl" includes both enantiomers of alkylsulfanyl. 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", "alkylsulfonyl" and the like, are defined analogously to the above examples. Examples of "alkylcarboxylic" include C(O)CH3With(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. "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 that the nitrogen atom of the amino group Pris is United to cycloalkylation and the hydrogen atom, and includes groups such as cyclopropylamino, cyclobutylamine, cyclopentylamine, cyclohexylamine. (Alkyl)(cycloalkyl)amino" means cycloalkylation, where the hydrogen atom of the amino group is replaced by alkylation, examples include groups such as (methyl)(cyclopropyl)amino, (butyl)(cyclobutyl)amino, (propyl)cyclopentylamine, (methyl)cyclohexylamino and the like. "Cycloalkenyl" includes groups such 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 alone, or in compound words such as "halogenated"includes fluorine, chlorine, bromine or iodine. The term "1-2 halogen" indicates that one or two positions available for Deputy may be occupied by halogen atoms, which are selected independently. In addition, when 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 F3C, ClCH2, CF3CH2and CF3CCl2.

The total number of carbon atoms in the group Deputy indicated by the prefix "Ci-Cj"where i and j denote, for example, from 1 to 3, for example, With1-C3alkyl denotes a group from methyl to propyl.

As indicated above, carbon is the group L, R1, R2, R3, R4, R10and X may contain an aromatic ring or ring system. Examples of aromatic rings or ring systems include phenyl ring, a 5 - or 6-membered heteroaromatic ring, an aromatic 8-, 9 - or 10-membered condensed carbobicyclic ring system and an aromatic 8-, 9 - or 10-membered condensed heterobicyclic ring system, each ring or ring system are optionally substituted. The term "optionally substituted" in connection with the above carbon groups L, R1, R2, R3, R4, R10and X refers to carbon groups, which are unsubstituted or have at least one non-hydrogen Deputy. These carbon groups can be substituted so many optional substituents, which can be provided by replacing the hydrogen atom of the non-hydrogen substituents on any available carbon atom or nitrogen. Usually the number of optional substituents (when present) ranges from one to four. Example phenyl, optionally substituted by one to four substituents is the ring, represented as U-1 in Annex 1, where Rvrepresents the non-hydrogen substituent and r is an integer from 0 to 4. Examples aromatic the ski 8-, 9 - or 10-membered condensed carbobicyclic ring systems, optionally substituted by one to four substituents include naftalina group, optionally substituted by one to four substituents, represented as U-85, and 1,2,3,4-tetrahydronaphthalene group, optionally substituted by one to four substituents, represented as U-86 in Appendix 1, where Rvrepresents any substituent and r is an integer from 0 to 4. Examples of 5 - or 6-membered heteroaromatic ring, optionally substituted by one to four substituents include the rings U-2 through U-53, shown in Appendix 1, where Rvrepresents any substituent and r is an integer from 1 to 4. Examples of aromatic 8-, 9 - or 10-membered condensed heterobicyclic ring systems, optionally substituted by one to four substituents include patterns from U-54 to U-84, are provided in Appendix 1, where Rvrepresents any substituent and r is an integer from 0 to 4. Other examples L and R include benzyl group, optionally substituted by one to four substituents, represented as U-87, and benzoyloxy group, optionally substituted by one to four substituents, represented as U-88 in Appendix 1, where Rvrepresents any substituent and r submitted is an integer from 0 to 4.

Although the groups Rvshown in structures from U-1 to U-85, it should be noted that their presence is not necessary, since they are optional substituents. The nitrogen atoms that require substitution to fill their valence, substituted N, or Rv. It is noteworthy that some of the group U can be replaced by only less than 4 groups of Rv(for example, U-14, U-15, U-18 and U-21 and U-32 U-34 can be replaced by only one group, Rv). It should be noted that, when the connection point between (Rv)rand U is illustrated as floating, (Rv)rcan be attached to any available carbon atom or nitrogen atom of the group U. it Should be noted that when the attachment point on the group U is illustrated as floating, the group U can be attached to the rest of the structure of formulas 1 and 2 through any available carbon atom of the group U by replacing a hydrogen atom.

Appendix 1

As indicated above, the carbon group L, R1, R2, R3, R4, R10and X may contain saturated or partially saturated carbocyclic and heterocyclic rings, which may be further optionally substituted. The term "optionally substituted" in connection with the above carbon groups L and R refers to carbon groups, which are unsubstituted or have at least one non-hydrogen Deputy. These carbon groups can be substituted so many optional substituents, which can be provided by replacing the hydrogen atom of the non-hydrogen substituents on any available carbon atom or nitrogen. Usually the number of optional substituents (when present) ranges from one to four. the reamers saturated or partially saturated carbocyclic rings include optionally substituted C 3-C8cycloalkyl and optionally substituted C3-C8cycloalkyl. Examples of saturated or partially saturated heterocyclic rings include 5 - or 6-membered non-aromatic heterocyclic ring, optionally containing one or two annular member selected from the group consisting of C(=O), S(O) or S(O)2not necessarily replaced. Examples of such carbon groups L, R1, R2, R3, R4, R10and X include those shown as structure from G-1 to G-35 in Appendix 2. It should be noted that when the attachment point on the specified group G is illustrated as floating, the group G can be attached to the rest of the structure of formula 1 or 2 through any available carbon atom or nitrogen group G by replacing a hydrogen atom. Optional substituents may be attached to any available carbon atom or nitrogen by replacement of a hydrogen atom (these substituents are not shown in Appendix 2, since they are optional substituents). It should be noted that, when G contains a ring selected from the structures from the G-24 to G-31, G-34 and G-35, Q2can be selected from O, S, NH or substituted n

Annex 2

It is noteworthy that the carbon group L, R1, R2, R3, R4, R10and X can be optionally substituted. As noted above, the carbon group L, R1, R2, R3, R4, R10and X may typically contain, among other groups, the group U or the group G, is additionally optionally substituted by one to four substituents. Thus, the carbon group L, R1, R2, R3, R4, R10and X can have a U or G is selected from the structures from U-1 to U-88 or from G-1 to G-35, and optionally substituted by additional substituents, including from one to four groups U or G (which may be the same or different), and the main group U or G, and substituting U or G can be further optionally substituted. Particularly notable are the carbon group L containing U, optionally substituted with one to three additional substituents. For example, L can be U-41.

Variants of the embodiment of the present invention include:

Variant embodiments 1. The method of obtaining the compounds of formula 1, where the molar ratio of bromine to the compound of formula 2 is from about 3:1 to about 1:1.

Variant of embodiment 2. The method according to the variant of embodiment 1, where the molar ratio of bromine to soedinenii formula 2 is from about 2:1 to about 1:1.

Variant of embodiment 3. The method according to the variant of embodiment 2, where the molar ratio of bromine to the compound of formula 2 is from about 1.5:1 to about 1:1.

Variant of embodiment 4. The method of obtaining the compounds of formula 1, where the bromine is added in the form of gas to the compound of formula 2.

Variant of embodiment 5. The method according to the variant of embodiment 4, where gaseous bromine diluted with an inert gas.

Variant of embodiment 6. The method according to the variant of embodiment 5, where the inert gas is nitrogen.

Variant of embodiment 7. The method according to the variant of embodiment 5, where the molar ratio of inert gas to the bromine is from about 50:1 to 2:1.

Variant of embodiment 8. The method according to the variant of embodiment 7, where the molar ratio of inert gas to the bromine is from about 30:1 to 4:1.

Variant of embodiment 9. The method of obtaining the compounds of formula 1, where the temperature is above about 100°C.

Variant of embodiment 10. The method according to the variant of embodiment 9, where the temperature is above about 120°C.

Variant of embodiment 11. The method of obtaining the compounds of formula 1, where the temperature is below about 180°C.

Variant of embodiment 12. The method according to the variant of embodiment 11, where the temperature is below about 150°C.

Variant of embodiment 13. The method according to the variant of embodiment 12, where the temperature is below about 140°C.

Variant of embodiment 14. SPO is about obtaining the compounds of formula 1, where the base is combined with a compound of formula 2 or before, or after contact with bromine.

Variant of embodiment 15. The method according to the variant of embodiment 14, where the base is selected from tertiary amines (including optionally substituted pyridine) and inorganic bases.

Variant of embodiment 16. The method according to the variant of embodiment 15, where the base is calcium carbonate and the amount of base is from about 0 to 10.0 equivalents relative to the bromine.

Variant of embodiment 17. The method according to the variant of embodiment 16, where the amount of base is from about 0 to 4.0 equivalents relative to the bromine.

Variant of embodiment 18. The method according to the variant of embodiment 15, where the amount of base is from about 0 to 2.4 equivalents relative to the bromine.

Variant of embodiment 19. The method of obtaining the compounds of formula 1, where the solvent is combined with the compound of formula 2 for the formation of the mixture prior to contacting with bromine.

Variant of embodiment 20. The method according to the variant of embodiment 19, where the solvent is optionally halogenated hydrocarbon with a boiling point higher than 100°C.

Variant of embodiment 21. The method according to the variant of embodiment 20, where the solvent is optionally chlorinated aromatic hydrocarbon or dibromsalan.

A variant of the GP is osenia 22 . The method according to the variant of embodiment 21, where the solvent is tert-butylbenzoyl, chlorobenzene or 1,2-dibromethane.

Variant of embodiment 23. The method according to the variant of embodiment 22, where the solvent is tert-butylbenzoyl.

Variant of embodiment 24. The method according to the variant of embodiment 22, where the solvent is chlorobenzene.

A variant embodiment 24b. The method according to any of the variants of embodiment 19-24, where the temperature close to the boiling temperature of the solvent.

Variant of embodiment 25. The method of obtaining the compounds of formula 1, where the molar equivalents of the solvent with respect to the compound of formula 2 is from about 5:1 to 50:1.

Variant of embodiment 26. The method according to the variant of embodiment 25, where the molar equivalents of the solvent with respect to the compound of formula 2 is from about 8:1 to 40:1.

Variant of embodiment 27. The method according to the variant of embodiment 26, where the molar equivalents of the solvent with respect to the compound of formula 2 is from about 10:1 to 30:1.

Variant of embodiment 28. The method of obtaining the compounds of formula 1 where X is halogen, OR3or optionally substituted carbon group.

Variant of embodiment 29. The method according to the variant of embodiment 28, where X is halogen or1-C4halogenated.

Variant of embodiment 30. The method according to the variant is oblasenia 29, where X is Br or CF3.

Variant of embodiment 31. The method according to the variant of embodiment 30, where X is Br.

Variant of embodiment 32. The method according to the variant of embodiment 28, where X represents OR3.

Variant of embodiment 33. The method according to the variant of embodiment 32, where R3represents N or C1-C4halogenated.

Variant of embodiment 34. The method according to the variant of embodiment 33, where R3is CF2H or CH2CF3.

Variant of embodiment 35. The method according to the variant of embodiment 32, where R3is N.

Variant of embodiment 36. The method of obtaining the compounds of formula 1, where L represents a phenyl ring or a 5 - or 6-membered heteroaromatic ring, optionally substituted by 1-3 R5.

Variant of embodiment 37. The method according to the variant of embodiment 36, where L represents pyridinyl or phenyl, optionally substituted by 1-3 R5and each R5independently represents halogen or1-C4halogenated.

Variant of embodiment 38. The method according to the variant of embodiment 37, where L is

Variant of embodiment 39. The method according to the variant of embodiment 38, where Z is N or CR9and R9represents H, halogen or1-C4halogenated.

Variant of embodiment 40. The method according to the variant of the GP is osenia 39, where Z is N.

Variant of embodiment 41. The method according to the variant of embodiment 40, where each R5independently represents halogen or CF3.

Variant of embodiment 42. The method according to the variant of embodiment 41, where the ring is substituted at position 3 by the radical R5that represents halogen.

Variant of embodiment 43. The method according to the variant of embodiment 42, where n is equal to 1.

Variant of embodiment 44. The method according to the variant of embodiment 43, where R5is Br or Cl.

Variant of embodiment 45. The method according to the variant of embodiment 39, where Z represents CR9.

Variant of embodiment 46. The method according to the variant of embodiment 45 where R9represents H, halogen or CF3.

Variant of embodiment 47. The method according to the variant of embodiment 46, where R9represents halogen.

Variant of embodiment 48. The method according to the variant of embodiment 47, where R9is Br or Cl.

Variant of embodiment 49. The method of obtaining the compounds of formula 1, where R1represents N or C1-C4alkyl.

Variant of embodiment 50. The method according to the variant of embodiment 49, where R1is N.

Variant of embodiment 51. The method of obtaining the compounds of formula 1, where R2represents H, CN, C1-C4alkyl, CO2R10, NO2or SO2R4and R10represents N or C1-C4

Variant of embodiment 52. The method according to the variant of embodiment 51, where R2is CO2R10.

Variant of embodiment 53. The method according to the variant of embodiment 52, where R10represents N or C1-C4alkyl.

Variant of embodiment 54. The method according to the variant of embodiment 53, where R10is1-C4alkyl.

Variant of embodiment 55. The method according to the variant of embodiment 54, where R10represents methyl or ethyl.

Variant of embodiment 56. The method according to the variant of embodiment 51, where R4is1-C4alkyl or optionally substituted phenyl.

Variant of embodiment 57. The method according to the variant of embodiment 56, where R4represents methyl, phenyl or 4-tolyl.

Additional options embodiments include a method for obtaining compounds of formula 3 using the compounds of formula 1A, obtained by the method according to any of the variants of embodiment 1-57.

Notable are the following options of the incarnation.

Variant embodiments And. The method of obtaining the compounds of formula 1, where

X represents halogen, OR3or1-C4halogenated,

L represents a phenyl ring or a 5 - or 6-membered heteroaromatic ring, optionally substituted by 1-3 R5,

R1represents H,

R2represents H, CN, C1-C4alkyl, CO 2R10, NO2or SO2R4,

R3represents N or C1-C4halogenated,

R4is1-C4alkyl or optionally substituted phenyl,

each R5independently represents halogen or1-C4halogenated, and

R10represents N or C1-C4alkyl.

A variant embodiment In. The method according to variant embodiments of a compound of formula 1 is represented by formula 1A

and the compound of formula 2 is represented by formula 2A

Z is N or CR9,

R9represents H, halogen or1-C4halogenated, and

n represents an integer from 0 to 3.

A variant embodiment With. The method according to the variant embodiment In which

X represents Br or CF3,

Z is N

each R5independently represents halogen or CF3and

R10represents methyl or ethyl.

Variant of embodiment D. The method according to the variant embodiment In which

X represents OR3,

R3represents N or C1-C4halogenated, and

R10represents N or C1-C4alkyl.

Variant of embodiment E. The method according to the variant of embodiment D, where

X is HE, OCF2H or OCH2CF3,

Z N

each R5independently represents halogen or CF3and

R10represents methyl or ethyl.

Variant of embodiment F. The method of obtaining the compounds of formula 1, where the temperature is from about 120°C. to 140°C.

Variant of embodiment G. The method of obtaining the compounds of formula 1, where the base is combined with a compound of formula 2 or before, or after contact with bromine and molar equivalents of base relative to the bromine is from about 0:1 to 4:1.

Variant of embodiment N. The method of obtaining the compounds of formula 1, where the molar equivalents of bromine relative to the compound of formula 2 is from about 2:1 to 1:1.

Variant of embodiment I. The method of obtaining the compounds of formula 1, where the solvent is combined with the compound of formula 2 for the formation of the mixture prior to contacting with bromine and temperature close to the boiling temperature of the solvent.

Variant of embodiment J. The method of obtaining the compounds of formula 1, where the bromine is added in the form of gas to the compound of formula 2 and gaseous bromine diluted with an inert gas.

A variant embodiment For. The method of obtaining the compounds of formula 3

where

X represents halogen, OR3or1-C4halogenated,

Z is N or CR9,

R3represents N or C1-C 4halogenated,

each R5independently represents halogen or1-C4halogenated,

R6is CH3, F, Cl or Br, and

R7represents F, Cl, Br, I, CN or CF3,

R8ais1-With4alkyl,

R8brepresents N or CH3,

R9represents H, halogen or1-C4halogenated, and

n represents an integer from 0 to 3,

with the use of the compounds of formula 1A

where R10represents N or C1-With4alkyl,

which is characterized by obtaining the compounds of formula 1A method according to the variant embodiment of the Century

Variant of embodiment L. The method according to the variant of embodiment, where

Z is N

each R5independently represents Cl, Br or CF3,

one R5is in position 3, and

R10represents methyl or ethyl.

Variant of embodiment M. The method according to the variant of embodiment L, where X is Br, n is 1 and R5is Cl.

As shown in comparative example 1, attempts to oxidize 2-pyrazoline formula 2 to pyrazoles of formula 1, using bromine as the oxidant at a temperature close to ambient conditions often lead to side reactions involving bromination substituent on the ring pyrazoline or pyrazole. Was is detected, the contacting 2-pyrazoline formula 2 with bromine at about 80°C or higher can provide with excellent selectivity corresponding pyrazole of formula 1, as shown in figure 1.

Scheme 1

The reaction is carried out by bringing into contact 2-pyrazoline formula 2, usually in the form of a solution in an inert solvent, with bromine at elevated temperatures. By-product hydrogen bromide is removed either chemically, for example, by addition of an appropriate base, or physically, for example, by bubbling the reaction mixture with an inert gas. After completion of the reaction product are methods known to experts in this field, for example, by crystallization or distillation.

The process can be conducted in a variety of inert solvents, preferably of low to moderate polarity. Suitable solvents include aliphatic hydrocarbons, haogenplast, aromatic solvents and mixtures of the above. Aliphatic hydrocarbon solvents include alkanes with a straight or branched chain, such as octane, Noonan, Dean, and the like, and mixtures of aliphatic hydrocarbons such as white spirit and naphtha. Halogenosilanes solvents include alkanes with a straight or branched chain, substituted by at least the ne halogen, such as 1,1,2,2-tetrachlorethane, 1,2-dibromoethane and the like. Aromatic solvents include benzene, optionally substituted by one or more substituents selected from halogen, tertiary alkyl and alkyl straight or branched chain, a fully substituted with halogen on the carbon atom attached to the benzene ring, and optionally substituted by halogen on other carbon atoms, for example, benzene, tert-butylbenzoyl, chlorobenzene, 1,2-dichlorobenzene, benzotrifluoride, benzotrichloride and the like. The optimal choice of solvent depends on the desired temperature and pressure process. If it is desired, the process may be carried out at higher than ambient, the pressure to raise the boiling point of the solvent. Low pressure can also be used. To facilitate the work, however, the preferred operating pressure is the ambient pressure, in this case, the boiling point of the solvent should be the same as the desired operating temperature or more. In one variant embodiment of the present invention the solvent is optionally halogenated hydrocarbon with a boiling point higher than 100°C. Particularly suitable solvents include tert-butylbenzoyl, chlorobenzene and 1,2-dibromethane. The molar ratio dissolve the I to the compound of formula 2 is usually from about 50:1 to 5:1, preferably from about 40:1 to 8:1 and most preferably from about 30:1 to 10:1.

According to this invention, the reaction temperature must be raised to a level favorable for oxidation during the completion of synthesized to maximize the output of the process. In one variant embodiment of the method according to this invention, the reaction temperatures are typically in the range from about 80°C. to 180°C. In additional embodiments, the embodiment of the temperature range from about 100°C to 150°C and about 120°C. to 140°C.

In this invention the oxidizing bromine may be added either in liquid form or in the form of gas. In one variant embodiment of gaseous bromine may be diluted with an inert gas, such as nitrogen, helium, argon and the like. The bromine can be added within such a short period, as it allows the removal of hydrogen bromide. In one variant embodiment, for practical purposes, the time of addition of bromine is usually from 0.5 to 20 hours, preferably from 0.5 to 10 hours and most preferably from 1.5 to 4 hours. Although there are a wide range of ratios of the reagents, the nominal molar ratio of bromine to the compound of formula 2 is usually from about 3 to 1, preferably from about 2 to 1 and most preferably from about 1.5 to 1.

As is eacli according to this invention as a by-product formed hydrogen bromide, which in other circumstances could be in contact with the centers of the main character in the compounds of formulas 1 and 2, or to influence the oxidation reaction, the method is usually carried out by removing hydrogen bromide from the solution chemically by adding a suitable inorganic or organic bases, and/or by bubbling an inert gas and/or heating at the boiling point under reflux. Can be used various inorganic bases, including the oxides or carbonates of alkaline or alkaline earth metals such as sodium carbonate, potassium carbonate, calcium carbonate, calcium oxide or the like. Can be used various organic bases, including tizamidine amines, such as triethylamine, N,N-diisopropylethylamine, N,N-diethylaniline or the like, or heteroaromatic bases, such as pyridine, picoline, imidazole or the like. In one variant embodiment of the present invention, calcium carbonate is a suitable basis for reasons of cost and availability. The base is usually added before the addition of bromine. As shown in figure 1, during the formation of each molar equivalent of pyrazole 1 is formed 2 molar equivalent of by-product hydrogen bromide. Therefore, at least 2 molar equivalents of base for each mole of the compounds the formula ia 2 required to neutralize the by-product hydrogen bromide. The excess can be used within the limits of economic feasibility. In one variant embodiment of the nominal molar equivalent ratio downloadable inorganic bases to download the bromine is from about 2 to 10. In another variant embodiment of the nominal molar equivalent ratio of the loaded organic bases to download the bromine is from about 2 to 4.

By-product hydrogen bromide can be removed from the reaction mixture by physical means, for example, by bubbling the solution with an inert gas or by heating at the boiling point under reflux. Options suitable inert gases include nitrogen, helium, argon and carbon dioxide. The inert gas may be mixed with bromine before introduction into the reactor. The quantity of inert gas should be sufficient to effectively remove hydrogen bromide at the rate at which it is formed. The number of required inert gas depends on the solvent, the reaction temperature and rate of addition of bromine. In one variant embodiment of the present invention nominal molar ratio of inert gas to the bromine is usually from about 50:1 to 2:1, and an inert gas is added to the same period of time when there is the addition of bromine. In additional option is oblasenia nominal molar ratio of inert gas to the bromine is from about 30:1 to 4:1. When heated under reflux at the boiling temperature of the reaction solvent evaporated the solvent itself may function as an inert gas to remove hydrogen bromide. In one variant embodiment of the nominal molar ratio of the vaporized solvent to the bromine above about 5 during the addition of bromine. In additional embodiments, embodiments of the ratio of above about 10 and below about 50 vaporized solvent to the bromine during the addition of bromine.

According to the method according to this invention, when the by-product hydrogen bromide is removed from the reaction mixture by bubbling the solution with an inert gas or by heating at the boiling point under reflux, the molar ratio of the base present in the reaction mixture, the bromine may be less than 2:1. The nominal molar ratio of the base added to the reaction mixture, the bromine is usually from about 0 to 10, preferably from about 0 to 4, and most preferably from about 0 to 2.4.

According to this invention, the solvent is usually combined with a compound of formula 2 for the formation of the mixture and heated at boiling temperature under reflux before contacting with bromine. When bromine is added to the reaction mixture, a by-product of the reaction of methyl hydrogen delete the Ute while bubbling the reaction mixture with an inert gas and heated at the boiling point under reflux, the reaction temperature is, therefore, close to the boiling temperature of the solvent. Therefore, in the variant embodiment according to this invention, the solvent is combined with the compound of formula 2 to obtain a mixture prior to contacting with bromine, and the reaction temperature close to the boiling temperature of the solvent.

The reaction is usually complete within a period of from one hour to one day, the reaction can be monitored by methods known to experts in this field, such as thin layer chromatography and spectral analysis1H-NMR. Received pyrazoles of formula 1 can be isolated from the reaction mixture by methods known to experts in this field, including extraction, crystallization and distillation.

As shown in scheme 2, the compound of formula 1A is a subspecies of the compounds of formula 1 where X, R5, R10and Z have the values listed above. The compounds of formula 1A can be obtained from corresponding compounds of formula 2A, which are a subspecies of compounds of formula 2, the method according to this invention, as described above.

Scheme 2

The compounds of formula 2 can be obtained using a wide variety of modern methods of synthesis known to the experts in this field. As a rule, the compounds of formula 2, where X represents ug is irodou group, can be obtained by interaction of α,β-unsaturated ketones of formula 4 and hydrazines of formula 5, as shown in outline in figure 3.

Scheme 3

where X represents a carbon group

The compounds of formula 2b can be obtained by contacting compounds of formula 4A with hydrazines of the formula 5 (Scheme 4). The compounds of formula 2b can then be alkylated with alkylating agent Lg-R3formula 6 in the presence of a suitable base to obtain the compounds of formula 2C. The alkylation reaction is usually carried out in a solvent, which may include ethers, such as tetrahydrofuran or dioxane, and polar aprotic solvents such as acetonitrile, N,N-dimethylformamide and the like. The base can be selected from inorganic bases such as potassium carbonate, sodium hydroxide or sodium hydride. Preferably the reaction is carried out using potassium carbonate or N,N-dimethylformamide or acetonitrile as solvent. In the alkylating agent Lg-R3Lg is nucleofug (i.e. leaving group such as halogen (such as Br, I), OS(O)2CH3(methanesulfonate), OS(O)2CF3, OS(O)2Ph-p-CH3(p-toluensulfonate) and the like. The product of formula 2C can be allocated by traditional methods, such as extraction.

As shown in General scheme 5, compounds of formula 2d, where X is halogen, can be obtained by halogenoalkanes from the corresponding compounds of formula 2b.

Scheme 5

The halogenation reagents that can be used include oxychloride phosphorus, trihalogen phosphorus, pentachloride phosphorus, thionyl chloride, dialoginterface, dehalogenation, oxalicacid and phosgene. Preferred are oxychloride phosphorus and pentavalent phosphorus. 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. 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 possible.

Alternatively, the compounds of formula 2d, where X is halogen, can be obtained by treating the corresponding compounds is of the formula 2d, where X is another halogen (such as Cl to obtain the compounds of formula 2d, where X is Br), hydrogen bromide or hydrogen chloride, respectively. In this way the Deputy halogen X on the initial compound of formula 2d replace Br or Cl from hydrogen bromide or hydrogen chloride, respectively. The parent compound of formula 2d, where X represents Cl or Br, can be obtained from corresponding compounds of formula 2d, as already described.

Basic reference to obtain 2-pyrazolines see Levai, A., J. Heterocycl. Chem.2002, 39(1), pp 1-13; El-Rayyes, NR, Al-Awadi N.A., Synthesis1985, 1028-22 and references cited therein. Since the compounds of formula 2A are a subspecies of compounds of formula 2, where X, R5, R10and Z have the abovementioned meanings, compounds of formula 2A can be obtained by methods already described previously in schemes 3, 4 and 5. Additional references for obtaining compounds of formula 2A, see PCT publication WO 2003/016283 and WO 2004/011453.

It is clear that some reagents and reaction conditions described above to obtain compounds of formula 2 may be incompatible with specific functional groups present in the intermediate compounds. In such cases, the inclusion in the process of synthesis sequences protection/unprotect or interconversion of functional groups will help to achieve want is lnyh products. The application and the choice of protective groups will be apparent to a person skilled in the field of chemical synthesis (see, for example, Greene, T. W., Wuts, P.G.M. Protective Groups in Organic Synthesis. 2nded., Wiley: New York, 1991). The specialist should be understood that, in some cases, after the introduction of a given reagent as it is specified on any individual scheme, it may be necessary to conduct not specified in detail additional routine synthesis step, to complete the synthesis of compounds of formula 2. The specialist should also be understood that it may be necessary to carry out the combination of stages, illustrated in the above schemes, in a different order than expected the particular sequence presented to obtain the compounds of formula 2. The specialist should also be understood that the described herein the compounds of formula 2 and intermediate compounds can be subjected to various electrophilic, nucleophilic, radical, ORGANOMETALLIC, oxidation and reductive reactions for attaching substituents or modification of present deputies.

It is assumed that no additional development specialist in this field, using the preceding description can utilize the present invention in its entirety. The following examples focus on bromirovanii 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-digitron-pyrazole-5-carboxylate, as shown in outline in scheme 6. The formation of three products (formulas 8, 9 and 10)when bromine is used as oxidant for the oxidation of 2-pyrazoline formula 7. These examples should be construed as merely explanatory and not limiting of the disclosure in any way.

Scheme 6

HPLC (HPLC means high performance liquid chromatography. Range1H-NMR is presented in ppm lower field 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 "Sirs" means broad singlet.

COMPARATIVE EXAMPLE 1

Bromination of 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate at a temperature close to ambient temperature

In chetyrehosnuju flask of 2 l, equipped with a mechanical stirrer, thermometer, addition funnel, reflux condenser and inlet for nitrogen, download 50.0 g (0,150 mol) ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxyla (for more, see WO 2003/16283, example 9), 500 ml of dichloromethane, 200 ml of water and 15.0 g (0,179 mol) of sodium bicarbonate. A two-phase mixture is treated dropwise over a period of about 20 minutes of 25.0 g (0,156 mol) of bromine, dissolved in 25 the l dichloromethane. The temperature of the reaction mass increases from 19 to 25°C, and the gas is released rapidly during the addition. The obtained orange mixture was kept at ambient conditions for 1 hour. The reaction mass is transferred into a separating funnel. The dichloromethane layer is separated, dried over magnesium sulfate, filtered and then concentrated on a rotary evaporator. The obtained brown oil (59,9 g) contains, as defined by the1H-NMR of ethyl 3-bromo-1-(5-bromo-3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (91% by weight, formula 8) with ethyl 3-bromo-1-(5-bromo-3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (2%, formula 9), ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (2%, formula 10) and dichloromethane (5%).

The compound of formula 8:

1H-NMR (DMSO-d6)δ of 8.25 (d, 1H), 8,16 (d, 1H), 5,16 (DD, 1H), 4,11 (kV, 2H), 3,61 (DD, 1H, and 3.31 (DD, 1H)and 1.15 (t, 3H).

The compound of formula 9:

1H-NMR (DMSO-d6)δ 8,76 (d, 1H), 8,73 (d, 1H), 7,37 (s, 1H), 4,18 (kV, 2H), 1,12 (t, 3H).

The compound of formula 10:

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 1

Bromination of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate in the presence of pyridine

And: Apparatus for adding gaseous bromine

Experimental apparatus for examples 1A-1C includes a flow meter, syringe pump, a mixing chamber, a trap, SK is ubber and 2-necked flask of 10 ml, in one throat which is inserted water-cooled condenser and covered with Teflon® thermocouple wires passing through the condenser to the measuring device. The mixing chamber allows you to mix bromine with gaseous nitrogen before introduction of a 2-necked flask, which serves as the reaction vessel. The mixing chamber consists of a glass vial 7 ml, closed with a rubber membrane. Nitrogen gas passes through the flow meter and tubing fluoropolymer Teflon® (1.6 mm O.D.)penetrating the rubber membrane of the mixing chamber. Bromine injected from the syringe pump into the mixing chamber through a needle of the syringe, these rubber membrane mixing chamber. A mixture of bromine and nitrogen exits the mixing chamber through a tube of Teflon®penetrating the rubber membrane and flows through a tube penetrating the rubber membrane on the other throat 2-necked flask so that the end of the tube is submerged below the surface of the reaction solution. The reaction flask is heated using an oil bath, and the temperature of the reaction is followed by a measuring device with a thermocouple. Tube connected with the top of the condenser, directs exhaust gaseous nitrogen and unfused pairs in the trap and then to a scrubber containing an aqueous solution of sodium bisulfite, to capture by-product hydrogen bromide and a-l is Bo excess bromine.

EXAMPLE 1A

In the presence of pyridine

In dvuhgolosy flask in the above-described apparatus of the type 0,500 g (1,503 mmol) ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate, 0,256 g (3,23 mmol) of pyridine and of 5.05 g of chlorobenzene and heated to 115°C. Bromine (0,265 g, 85 μl, of 1.66 mmol) injected from the syringe into the mixing chamber for 2 h (i.e. 40 μl/h), while nitrogen is passed through the mixing chamber into the reaction mixture at a speed of 0.41 ml/s Flow of nitrogen supports the following half hour. Painted in orange color of the reaction mixture is cooled and then analyzed by quantitative HPLC using O-terphenyl (61,4 mg) as internal standard. Analytical samples for HPLC analysis prepared by adding a weighted O-terphenyl to the reaction mixture and 5 ml of dimethyl sulfoxide to dissolve all of precipitated salt. Aliquot the sample 20 ál of the resulting solution is taken and diluted with 1 ml of acetonitrile and filtered through a 0.2 μm Frit to obtain the analytical sample for HPLC. The output is presented in mol.%. HPLC shows that the obtained solution, other than chlorobenzene and pyridine, contains 89% ethyl 3-bromo-1-(5-bromo-3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (formula 10) and 9% of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (formula 7).

EXAMPLE 1B

In the presence of carbonate calc the I

In dvuhgolosy flask of 10 ml in the above-described apparatus equipped with a stirrer to facilitate mixing, add 0,500 g (1,507 mmol) ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate, 0,507 g (of 5.06 mmol) of calcium carbonate and of 5.00 g of chlorobenzene and heated to 130°C. Bromine (0,265 g, 85 μl, of 1.66 mmol) injected from the syringe into the mixing chamber for 2 h (40 μl/h), while nitrogen is passed through the mixing chamber into the reaction mixture at a speed of 0.41 ml/s Flow of nitrogen supports the following 10 minutes. The reaction mixture is cooled and then analyzed by quantitative HPLC using O-terphenyl (51,1 mg) as internal standard. HPLC shows that the obtained solution, other than chlorobenzene, contains 96% ethyl 3-bromo-1-(5-bromo-3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (formula 10) and 2% ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (formula 7).

EXAMPLE 1C

By bubbling with nitrogen and without the addition of base

In dvuhgolosy flask of the above described apparatus is added 0.25 g (0,76 mmol) ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate and 2.5 g of chlorobenzene and heated to 130°C. Bromine (0,233 g, 75 µl of 1.46 mmol) injected from the syringe into the mixing chamber for 3 h (15 μl/h), while nitrogen is passed continuously through a mixing chamber in reacciona the mixture at a speed of between 0.46 ml/s The reaction mixture is cooled and then analyzed by quantitative HPLC using O-terphenyl (32.7 mg) as internal standard. HPLC shows that the obtained solution, other than chlorobenzene, contains 88% of ethyl 3-bromo-1-(5-bromo-3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (formula 10) and 0% of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (formula 7).

EXAMPLE 3

Bromination of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate under different reaction conditions

Following General procedure used for examples 3-1 to 3-38. In a flat-bottomed cylindrical glass vessel (15 mm I.D. 80 mm) load ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate, chlorobenzene, and optionally calcium carbonate. Glass vessel then supply a magnetic stirrer, water cooled condenser and covered with Teflon® thermocouple for temperature measurement. The reaction mixture is heated to the desired temperature in the oil bath and a stream of nitrogen at a particular flow rate is passed through a tube made of Teflon®, is inserted into the reaction mixture. Bromine adds with a controlled rate from a syringe attached to a syringe pump, a syringe connected through the T-shaped connector with a tube of Teflon®, which carries a stream of nitrogen, and thus, bromine delivered in vapor phase in actionnow mixture. The exhaust gases are passed through a water trap, which is used to collect hydrogen bromide and any excess of bromine, which passes through the reaction mixture. After adding all of the bromine, the reaction mixture is cooled, while maintaining the flow of nitrogen. The reaction mixture is produced for analysis by adding weighed amounts of dimethyl sulfoxide (4.3 to 4.4 g)containing a known amount of ortho-terphenyl as internal standard. After thorough mixing the aliquot sample from 7.5 to 15 μl of this mixture was diluted with 900 μl of acetonitrile was passed through a 0.2 μm filter and analyzed by the device for high-performance liquid chromatography Agilent 1100 series®. The amount of compounds of formula 7, of moles of solvent (chlorobenzene) and bromine with respect to the source connection of the formula 7, the speed of addition of the bromine, the molar equivalents of base (calcium carbonate) and nitrogen relative to the bromine, nitrogen flow, the reaction temperature and the reaction results, including the % conversion of starting compound of the formula 7 and % outputs compounds of formulas 10, 9 and 8, are listed in table 1 for each example. The output response of each connection of the reaction mixture indicated as mol.% for each example in table 1.

Table 1
Etc.The number Conn. 7Moth dissolve the user to connect. 7EQ. CaCO3to Br2EQ. Br2to Conn. 7The speed of adding Br2(µl/h)EQ. N2to Br2Consumption of N2(ml/min)The pace. (°C)% conversion Conn. 7Mol.% Conn. 10Mol.% Conn. 9Mol.% Conn. 8
3-11,00150,01,015434,011052,932,81,518,0
3-21,00150,41,4216220,011069,833,33,1 of 31.8
3-30,67220,01,01035to 12.011052,635,71,115,1
3-40,67231,01,2123420,011062,336,82,421,8
3-50,50301,21,07774,011050,836,80,813,5
3-60,50300,01,4 10854,011061,837,42,121,8
3-71,00160,91,48664,011068,839,94,517,7
3-81,00161,21,0391320,011059,545,93,38,3
3-90,50300,01,019264,011056,747,8 1,55,5
3-100,50290,01,0311620,011059,548,02,17,1
3-111,00150,01,454920,011073,348,210,311,4
3-120,67220,51,231164,011066,749,13,27,6
3-130,50300,9 1,4271920,011080,963,510,65,8
3-141,00160,01,2185320,012058,638,21,915,0
3-151,00161,01,21853to 12.012065,942,32,616,3
3-160,50270,01,031164,012065,1 56,91,03,2
3-170,50300,41,4108520,012077,760,9a 4.9the 10.1
3-180,67210,41,436144,0120to 89.575,34,61,7
3-190,67220,51,04312to 12.012084,377,72,62,3
3-201,0015 1,21,039134,013095,963,60,40,0
3-210,50270,01,07774,013070,563,60,70,0
3-221,00161,21,0154320,013078,067,01,20,0
3-231,00160,01,42162to 12.0130 92,369,38,11,4
3-240,50270,61,03116to 12.013088,774,20,32,5
3-250,50300,01,077720,0130of 87.074,30,10,0
3-261,00160,51,27474,013093,774,71,50,0
3-270,50 271,21,0192620,0130a 94.278,70,30,0
3-281,00160,01,0391320,013095,681,10,20,0
3-290,67230,81,414444,013092,381,22,71,0
3-301,00150,01,45494,0 130100,083,91,40,0
3-310,50270,91,427194,013098,684,50,70,0
3-321,00160,91,454920,013099,588,50,20,0
3-330,50270,91,4108520,013095,689,42,21,1
3-34 0,67210,01,458920,0130100,090,10,82,3
3-350,50270,01,4271920,0130of 99.190,30,70,0
3-360,59250,71,4421220,013099,292,60,00,0
3-370,60240,81,54312 20,013099,393,50,30,0
3-380,59250,71,4421220,0130100,094,90,00,0

The following abbreviations are used in table 2: t means tertiary, s means secondary, n means normal, i means ISO, Me means methyl, Et means ethyl, Pr means propyl, i-Pr means isopropyl and Bu means butyl. Table 2 illustrates the specific transformations to obtain compounds of the formula 1A compounds of formula 2A, according to the method according to this invention.

Utility

Selective oxidation of 2-pyrazolines bromine according to this invention can be used to produce a wide variety of compounds of formula 1, which are used as intermediates for obtaining agents for crop protection, pharmaceutical agents, and other fine chemicals. Among the soybean is ineni, obtained according to the method according to this invention, the compounds of formula 1A is particularly applicable for producing compounds of formula 3

where X, Z, R5and n have the above values, R6is CH3, F, Cl or Br, R7represents F, Cl, Br, I, CN or CF3, R8ais1-C4alkyl, and R8brepresents N or CH3.

The compounds of formula 3 are applicable as insecticides, as described, for example, in PCT publication no WO 01/015518. Obtaining compounds of formulas 2 and 3 are also described in WO 01/015518 and patent application U.S. 60/633899, filed December 7, 2004 [BA9343 US PRV], which are incorporated in this description by reference in their entirety.

The compounds of formula 3 can be obtained from corresponding compounds of formula 1A ways presented on figures 7-10.

Compounds of carboxylic acids of formula 1A where R10is H, can be obtained by hydrolysis of the corresponding compounds of esters of formula 1A where, for example, R10is1-C4alkyl. Carboxyl ester compounds can be converted into compounds of carboxylic acids in many ways, including nucleophilic cleavage in anhydrous conditions or hydrolytic methods involving the use of either acids or bases (for whom btra methods, see T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2nded., John Wiley & Sons, Inc., New York, 1991, pp 224-269). For compounds of formula 1A preferred base catalyzed hydrolytic methods. Suitable bases include 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 ester is subjected to saponification with the formation of sodium or potassium salt of carboxylic acid. Acidification with a strong acid, such as chloride-hydrogen or sulphuric acid, yields the carboxylic acid of formula 1A where R10represents N. The carboxylic acid may be selected, known in the art methods, including extraction, distillation and crystallization.

As illustrated in figure 7, the binding pyrazolylborate acid of formula 1A where R10represents H, with Anthranilic acid of formula 11 provides benzoxazine formula 12. In the method according to scheme 7 benzoxazine formula 12 is obtained directly by the sequential addition of methanesulfonanilide to pyrazolylborate acid of formula 1A where R10represents H, in the presence of a tertiary amine such as triethylamine or pyridine, followed by the addition of Anthranilic acid of formula 11, then the second added the m tertiary amine and methanesulfonanilide. This procedure usually gives good output benzoxazinone formula 12.

Scheme 7

where R5, R6, R7, X, Z and n have the meanings specified for formula 3.

An alternative way of obtaining benzoxazinones formula 12 is shown in scheme 8, it involves linking the acid chloride pyrazolylborate acid of formula 14 with sativum anhydride of the formula 13, in order to obtain directly benzoxazine formula 12.

Scheme 8

where R5, R6, R7, X, Z and n have the meanings specified for formula 3.

Solvents, such as pyridine or pyridine/acetonitrile are suitable for this reaction. The acid chlorides of formula 14 are available from the corresponding acids of formula 1A where R10represents H, using known methods, such as chlorination with thionyl chloride or oxalylamino.

The compounds of formula 3 can be obtained by the interaction benzoxazinones formula 12 with amines other8aR8bformula 15 as shown in scheme 9.

Scheme 9

where R5, R6, R7, R8a, R8b, X, Z and n have the meanings given above for formula 3.

The reaction can be carried out directly between them or in a wide variety of solvents, including clonicel, tetrahydrofuran, diethyl ether, dichloromethane or chloroform with optimum temperatures ranging from room temperature to the boiling point of the solvent under reflux. This basic reaction benzoxazinones with amines to obtain anthranilamide well documented in the chemical literature. For a review on the chemistry of benzoxazinone see Jakobsen et al., Bioorganic and Medicinal Chemistry2000, 8, 2095-2103 and quoted your link here. Cm. also, Coppola, J. Heterocyclic Chemistry1999, 36, 563-588.

The compounds of formula 3 can be also obtained by the method shown in scheme 10. Direct binding of compounds of the formula 11 with compounds of formula 1A where R10represents H, by using a suitable reagent combinations, such as methanesulfonate, gives anthranilamide formula 3.

Scheme 10

Whatever the means for the conversion of compounds of formula 1A in the compound of formula 3, the invention provides an effective method of obtaining the compounds of formula 3, which is characterized by obtaining the compounds of formula 1A method of obtaining the compounds of formula 1, as described above.

1. The method of obtaining the compounds of formula 1A

where X represents halogen or1-C4halogenated;
Z is N or CR9;
each is th R 5independently represents halogen or1-C4halogenated;
R9represents H, halogen or1-C4halogenated;
R10represents N or C1-C4alkyl and
n represents an integer from 0 to 3,
including:
contacting 2-pyrazoline formula 2A

where X, Z, R5, R9, R10and n have the above values,
with bromine in the environment of a suitable inert organic solvent at a temperature of from 80 to 180°C.

2. The method according to claim 1, where
X represents Br or CF3and Z is N
each R5independently represents halogen or CF3and
R10represents methyl or ethyl.

3. The method according to claim 1, where the temperature is between about 120 and 140°C.

4. The method according to claim 1, where the base combine with the compound of the formula 2A or before, or after contact with bromine and molar equivalents of base relative to the bromine is from about 0:1 to 4:1.

5. The method according to claim 1, where the molar equivalents of bromine relative to the compound of formula 2A is from about 2:1 to 1:1.

6. The method according to claim 1, where the solvent is combined with the compound of formula 2A for the formation of the mixture prior to contacting with bromine and temperature close to the boiling temperature of the solvent.

7. The method according to claim 1, where the bromine is added in the form of gas to travel the formula 2A and gaseous bromine diluted with an inert gas.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel amide derivatives of general formula [1] in any of versions (A) or (B), or its pharmaceutically acceptable salt, which possess properties of tyrosinkinase BCR-ABL inhibitor. Amide derivative of general formula [1] represents compound: , where according to Version (A) R1 represents any of the following groups (1)-(3): (1) -) -CH2-R11 [R11 represents saturated 4-6 member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom, which is substituted by group selected from group, consisting of oxo, -CH2-R111 (R111 represents saturated 5-member nitrogen-containing heterocyclic group), saturated 5-member nitrogen-containing heterocyclic group, aminomethyl, monoalkylaminomethyl, dialkylaminomethyl and (5-methyl-2-oxo-1,3-Dioxol-4-yl)methyl, and in addition, can be substituted by 1 or 2 similar or different substituents, selected from group, consisting of (C1-C4)alkyl, (C1-C4 alkoxycarbonyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, amino, carbamoyl], (2) -O-R12 [R12 represents saturated 4-6-member nitrogen-containing heterocyclic group]; and (3) - CH=R13 [R13 represents saturated 4-6-member nitrogen-containing heterocyclic group, which can contain additional nitrogen atom, and which can be substituted by 1-3 similar or different substituents, selected from group, consisting of oxo, (C1-C4)alkyl]; R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy and carbamoyl; R3 represents hydrogen, halogen; Het1 represents any of groups with the following chemical formulae [4] and [6]: [4] [6] [19] [10] Het2 represents pyridyl or pyrimidinyl. According to Version (B) R1 represents -CH2-R14 [R14 represents saturated 4-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, which can be substituted by 1-3 similar groups, selected from (C1-C4)alkyl] R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)acyl, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, nitro, carbamoyl, mono(C1-C4)alkylcarbamoyl, di(C1-C4)alkylcarbamoyl or cyano; R3 represents hydrogen or halogen; Het1 represents any of groups with the following chemical formulas [9] and [10], Het2 represents pyridyl.

EFFECT: invention can be applied for treatment of chronic myeloleukosis, acute lymphoblastic leukosis and acute myeloblastic leukosis.

6 cl, 89 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new derivatives of piperidine of formula I: , in which: R1 and R2 are selected from group, including alkyl, halogenalkyl, alkyl substituted with one or more hydroxy groups, -CN, alkynyl, -N(R6)2, - N(R6)-S(O2)-alkyl, -N(R6)-C(O)-N(R9)2, -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR5)-alkyl, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R9)2 and group , , , ,

provided that at least one of R1 and R2 stands for -CN or group , , , ,

W stands for =C(R8)- or =N-; X stands for -C(O)- or -S(O2)-; Y is selected from group, including -CH2-, -O- and -N(R6)-C(O)-, provided that: (a) atom of nitrogen of group -N(R6)-C(O)- is linked with X, and (b) if R1 and/or R2 stands for and Y stands for -O-, then X does not stand for -S(O2)-; Z stands for -C(R7)2-, -N(R6)-, or -O-; R3 is selected from group, including H and non-substituted alkyl; R4 stands for H; R5 stands for H or alkyl; R6 is selected from group, including H, alkyl, cycloalkyl and aryl; each R7 independently stands for H or alkyl; or each R7 together with circular atom of carbon, to which they are linked, as indicated, forms cycloalkylene ring; R8 is selected from group including H, alkyl, alkyl substituted with one or large number of hydroxygroups, -N(R6)2, -N(R6)-S(O2)- alkyl, -N(R6)-S(O2)-aryl, -N(R6)-C(O)-alkyl, -N(R6)-C(O)-aryl, alkylene-O-alkyl and -CN; R9 is selected from group including H, alkyl and aryl, or each R9 jointly with atom of nitrogen, to which, as indicated, they are linked, forms heterocycloalkyl ring; Ar1 stands for non-substituted phenyl; Ar2 stands for phenyll substituted with 0-3 substituents, selected from group including halogenalkyl; n equals 0, 1 or 2; and m equals 1, 2 or 3, and to their pharmaceutically acceptance salts and hydrates.

EFFECT: production of new biologically active compounds, having properties of antagonist of neurokinin receptor NK1.

35 cl, 60 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compound of general formula (I): , where Ar1 is a phenyl group substituted with 1-3 halogen atoms; Ar2 is a phenyl group which can be substituted with a halogen, alkoxyalkyl, alkoxyhalogenalkyl, or pyridyl group which can be substituted with halogenalkyl; X is -S-, -SO- or -SO2-; Y is a hydrogen atom, -NR1R2 (where R1 is a hydrogen atom, lower alkyl group or hydroxy group; and R2 is a hydrogen atom, lower alkyl group which can be substituted, lower alkanoyl group, alkoxycarbonyl group which can be substituted, lower alkoxy group which can be substituted, amino group which can be substituted; or R1 and R2 together with a nitrogen atom with which they are bonded form a piperidine, morpholine, azetidine or piperazine ring, which can be substituted wiht a hydroxy group) or -OR1', where R1 is a hydrogen atom); Z is an oxygen atom or sulphur atom; and R is a hydrogen atom or a lower alkyl group; or to salts thereof. The invention also relates to a medicinal agent and a pharmaceutical composition which inhibit production/secretion of β- amyloid protein, to use of said compounds to prepare a medicinal agent and to a method of treating diseases caused by abnormal production or secretion of β- amyloid protein.

EFFECT: novel compounds which can inhibit production/secretion of β- amyloid protein and which can be used in treating Alzheimer disease or Down syndrome are obtained and described.

30 cl, 136 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds and pharmaceutical compositions containing said compounds can inhibit 11β-hydroxysteroid dehydrogenase of the form 1 (11-BETA-HSD-1) and can be used to treat diseases such as type II sugar diabetes type and metabolic syndrome.

17 cl, 99 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or its pharmaceutically acceptable salt, where R1 and R2 each independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a hydroxyl group, a cyano group or a lower alkoxy; R3 independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano group; R4 independently denotes a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen atom, trifluoromethyl, hydroxyalkyl optionally substituted with a lower alkyl, aminoalkyl optionally substituted with lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano group; Q denotes a nitrogen atom; R5 and R6 each independently denotes a hydrogen atom, a lower alkyl, a halogen atom, a lower alkylsulfonyl, a lower alkylsulfanyl, alkanoyl, formyl, aryl, mono- or di-(lower) alkylcarbamoyl or mono- or di-(lower) alkylsulfamoyl; and further as indicated in the formula of invention. The invention also relates to a glucokinase activator containing the compound in paragraph 1 and to a therapeutic agent based on said compounds.

EFFECT: novel compounds which can be useful in treating and preventing diabetes and obesity are obtained and described.

29 cl, 227 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds and pharmaceutical compositions containing said compounds can inhibit 11β-hydroxysteroid dehydrogenase of the form 1 (11-BETA-HSD-1) and can be used to treat diseases such as type II sugar diabetes type and metabolic syndrome.

17 cl, 99 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel compounds of formula I: ,

to their synthesis method, a pharmaceutical composition based on said compounds and use of said compounds in making medicinal agents. Substitutes R1, R2, R4, R5, as well as values of A, B, D and n are given in the formula of invention.

EFFECT: obtaining novel compounds of formula I: ,

as well as their pharmaceutically acceptable salts which have inhibitory effect on cholesteryl ester transfer protein (CETP).

14 cl, 251 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of synthesising compounds of formula (I), which involves reacting compounds of formulae (II) and (III) and sulfonyl chloride in a suitable organic solvent in the presence of a base to form a formula (I) compound, where the solvent and/or base is combined with compounds of formulae (II) and (III). Described also are compounds of formula (III), which are used as initial compounds for this method. Radicals R1-R6 are as described in the formula of invention.

EFFECT: design of a cheap, more efficient, flexible and easy to implement method for synthesis of formula (I) compounds.

13 cl, 2 tbl, 20 ex

FIELD: medicine.

SUBSTANCE: new compounds of thienopyrazole are described with formula (1) , where R1 means non-substituted C3-C8-cycloalkyl group or tetrahydropyranyl, R2 means non-substituted C1-C3alkyl group, R3 means atom of hydrogen, R4 means various groups mentioned in invention formula. Compounds inhibit PDE 7 and, accordingly, increase cell level of cyclic adenosine monophosphate. Pharmaceutical composition is also described, as well as method for inhibition of PDE, methods for production of compound with formula (1), where R4 means CO2R7, and intermediate compounds.

EFFECT: possibility to use for treatment of various types of such diseases as allergic diseases, inflammatory diseases or immunological diseases.

20 cl, 138 tbl, 440 ex

FIELD: agriculture.

SUBSTANCE: substituted pyrazole-carbonic anilide derivatives of formula (I) are described, where R1 represents H, alkyl, alkyl carbonyl, alkenyl carbonyl, phenyl alkyl, phenyl carbonyl; R2 represents H, halogen, alkoxy; G represents alkyl, alkenyl; Z represents O; X represents H, halogen, alkyl; Y1 represents alkyl, alkenyl; Y2 represents halogen, C1-C6alkyl, m is equal to 1 or 2; and n is equal to 1, and their salts, acaricide for agriculture, such as pyrazole carbonic anilide derivatives of formula (I) and method for its application. Intermediate compound of formula (II) is also described, as well as 1.3-dimethyl-5-trifluoromethylpyrazole-4-carbonic acid.

EFFECT: improved use of new acaricides.

12 cl, 5 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel malononitryl derivatives of formula (I), which can be applied to fight pest insects. In formula (I) R1 represents hydrogen atom; R2 represents hydrogen atom; R represents hydrogen atom; R4 represents C1-C5-alkyl group substituted with at least one halogen atom, C2-C5-alkenyl group; R5 represents hydrogen atom, halogen atom, C1-C5-alkyl group; at least one of X1, X2 and X3 values represents CR6, the other represent nitrogen atoms; R represents hydrogen atom, halogen atom, cyanogroup, nitrogroup, formyl group, C1-C5-alkyl group optionally substituted with at least one halogen atom, C1-C5-alkyltiogroup, substituted with at least one halogen atom, C2-C6-alkylcarbonyl group substituted with at east one halogen atom, C2-C5-alkoxycarbonyl group or group (CH2)mQ, where m = 0, and Q stands for phenyl; and in case when one of R5 and R6 is bonded with two atoms in adjacent positions or two R6 are bonded with two atoms in adjacent positions, they can be bonded to each other in end positions with formation of C2-C6-alkandiyl group, or C4-C6-alkenediyl group. Invention also relates to composition and method used to fight pest-insects.

EFFECT: obtaining novel malononitryl derivatives of formula (I), which can be applied to fight pest-insects.

11 cl, 90 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) , where R1 and R2 are independently chosen from hydrogen, halogen, nitro, alkyl, alkylaryl and XYR5; X and Y are independently chosen from O and (CR6R7)n; R3 represents hydrogen, alkyl or M; M represents an ion, chosen from aluminium, calcium, lithium, magnesium, potassium, sodium, zinc or their mixture; Z represents CR4; R4 is chosen from hydrogen, halogen, alkyl, alkylaryl and XYR5; R5 is chosen from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R6 and R7 are independently chosen from hydrogen and alkyl; n is an integer from 1 to 6; at least one of R1 and R2 represents XYR5, and at least one of X and Y represents (CR6R7)n. The invention also pertains to the method of increasing concentration of D-serine and/or reducing concentration of toxic products of D-serine oxidation under the effect of DAAO in mammals, involving introduction into a subject of a therapeutically effective amount of a formula I compound, to the method of treating schizophrenia, treating or preventing loss of memory and/or cognitive ability, to the method of improving learning ability, method of treating neuropathic pain, as well as to a pharmaceutical composition, with DAAO inhibitory activity, based on these compounds.

EFFECT: obtained are new compounds and a pharmaceutical composition based on these compounds.

27 cl, 4 tbl, 72 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: 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

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to 1,3,5-trisubstituted derivatives of 4,5-dihydro-1H pyrazole of general formula (I) , in which symbols have values given in i.1 of invention formula, based on them pharmaceutical composition, novel intermediate compounds suitable for synthesis of said pyrazole derivatives. Compounds of formula (I) are antagonists of cannabinoid receptors CB1. Invention also relates to the application of formula (I) compounds for obtaining medications for treatment of group of diseases mediated by CB1, such as psychosis, anxieties, depression, memory impairments, food intake disorders, etc.

EFFECT: increased efficiency of composition and treatment method.

7 cl, 1 tbl, 3 ex

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