Method for synthesis of 5-hydroxy-4-thiomethylpyrazole compound

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of a 5-hydroxy-4-thiomethylpyrazole compound, where a pyrazole compound of general formula is reacted with a sulphur compound of general formula X-S(O)n-R (2) in the presence of a base and formaldehyde to form a 5-hydroxy-4-thiomethyl compound of general formula , where radicals and symbols in the said formulae are defined in the formula of invention.

EFFECT: easier synthesis of the desired 5-hydroxy-4-thiomethylpyrazole compound with high output in mild conditions in a single step without using special equipment, expensive catalyst or a transition metal etc, where the process can be carried out virtually without formation of hazardous wastes from a catalyst etc; owing to this, the method is environmentally safe and can be used in industry.

6 cl, 16 ex

 

The technical field to which the invention relates.

The present invention relates to a method for producing 5-hydroxy-4-timetemperature connection, which is used as an intermediate product in the manufacture of pharmaceutical and agricultural chemical products.

The level of technology

Obtained in the present invention 5-hydroxy-4-dimethylpyrazole connection is used as an intermediate product in the manufacture of pharmaceutical and agricultural chemical products.

To obtain 5-hydroxy-4-dimethylpyrazole compounds known method in which 4-chloromethylthiazole compound reacts with the sulfur compound (see Patent document 1).

4-chloromethylthiazole compound used as starting material for this reaction, can be obtained, for example, the synthesis of pyrazol compounds having a methyl group in position 4, with the reaction of cyclization of the corresponding complex of β-ketoesters with hydrazine, methyl group must be turned into chloromethylene group by chlorination. Next, to obtain 4-dimethylpyrazole connection, you need to mentioned chloromethylene group reacted with any organo-sulfur compound (see Patent document 1). However, this method is not what I satisfactory as an industrial method of producing 4-dimethylpyrazole connection since the reaction involves several stages and the output is not high because of the difficulty of implementing selective monohalogenated methyl group in position 4 of the pyrazole.

As for the method of producing 4-chloromethylthiazole as a starting material in the above-described method, there is also known a method of direct chlorotoluene pyrazol compounds are not substituted in position 4 (see non-Patent document 1). However, this method is problematic and difficult to implement as a method for industrial production, since the reaction produces by-product bis(CHLOROTHALONIL) ether, which represents a carcinogenic substance.

Moreover, the reaction of direct timestribune pyrazol compounds is not known.

Patent document 1: international patent publication WO 2004/013106.

Non-patent document 1: Journal of Chemical Society, pp 1205-1208 (1955).

Disclosure of inventions

The need arose in the way in which would be eliminated named disadvantages of conventional methods and with the help of which you could easily get 5-hydroxy-4-dimethylpyrazole connection with high output.

Given this need, the authors of the present invention made intensive studies method of producing 5-hydroxy-4-dimethylpyrazole connection and the result is unexpected the way found when 5-hydroxypyrazoles compound of the following formula (1) is introduced into the reaction with the sulfur compound of the following formula (2) in the presence of a base and formaldehyde, formed 5-hydroxy-4-dimethylpyrazole compound of the following formula (3). The present invention was made on the basis of this discovery.

According to the method of the present invention 5-hydroxy-4-dimethylpyrazole compound represented by the formula (3)can be obtained from 5-hydroxypyrazoles compounds represented by formula (1), with high yield in a single stage using a simple method under mild conditions without the use of special reaction equipment or expensive catalyst or transition metal. In the method of the present invention is practically no formation of harmful waste products from the catalyst or the transition metal, and thanks to this method is environmentally safe and is characterized by high industrial applicability.

In addition, according to the embodiment using the method of the present invention as a solvent water offers a more environmentally friendly way, characterized by a higher degree of industrial applicability.

The implementation of the invention

The present invention includes, as an example, the next incarnation[1]-[6].

[1] the Way to obtain 5-hydroxy-4-dimethylpyrazole connection, comprising the reaction of pyrazole represented by the formula [1]:

where R1denotes a hydrogen atom, alkyl group, aromatic

hydrocarbon group which may have a Deputy, or a heterocyclic group which may have a Deputy, and R2denotes an electron-withdrawing group with a sulfur compound represented by the formula [2]:

where X denotes a hydrogen atom or a metal, R3denotes an alkyl group, an aromatic hydrocarbon group which may have a Deputy, or a heterocyclic group which may have a Deputy, and n is 0 or 2, in the presence of a base and formaldehyde, resulting in a gain of 5-hydroxy-4-dimethylpyrazole compound represented by the formula [3]:

where R1, R2, R3and n have the same meanings as above.

[2] the Method of obtaining 5-hydroxy-4-dimethylpyrazole connection, comprising the reaction of pyrazole as described in [1], where n is equal to 0.

[3] the Method of obtaining 5-hydroxy-4-dimethylpyrazole connection, comprising the reaction of pyrazole as described in [1], where n is equal to 2.

[4] the Method of obtaining 5-hydroxy-4-dimethylpyrazole compounds include the third reaction of pyrazole, as described in any of [1]to[3], where the electron-withdrawing group represented by R2is triptorelin group.

[5] the Method of obtaining 5-hydroxy-4-dimethylpyrazole connection, comprising the reaction of pyrazole as described in any of [1]to[3], where the electron-withdrawing group represented by R2is cyanide group.

[6] the Method of obtaining 5-hydroxy-4-dimethylpyrazole connection, comprising the reaction of pyrazole as described in any of [1]to[3], where the electron-withdrawing group represented by R2is alkoxycarbonyl group, carboxyl group, or their salts with metals.

The best option of carrying out the invention

Below the present invention is described in detail. In the following text, unless otherwise stated, "parts" and "%"representing quantitative relationships based on weight.

The way to obtain 5-hydroxy-4-dimethylpyrazole connection

The present invention relates to a method for producing 5-hydroxy-4-dimethylpyrazole compounds represented by formula (3), comprising the reaction of 5-hydroxypyrazoles compounds represented by formula (1), with a sulfur compound represented by the formula (2), in the presence of a base and formaldehyde.

Isomer

5-Hydroxypyrazoles compound represented by the formula (1)used as and the initial material in the present invention, and 5-hydroxy-4-dimethylpyrazole compound represented by the formula (3), which is the product, can be represented in the form of keto-enol tautomers. In the present invention the connection of the source material and the product represented by the structures, based on the enol form as in formulas (1) and (3), but in practice the ratio of the components keto-enol tautomers sometimes varies, for example, from a solvent used to dissolve the connection, but even in this case, the original material or product in the method of the present invention include both isomers keto-enol form.

5-Hydroxypyrazoles connection

The following describes 5-hydroxypyrazoles compound represented by the formula (1)used in the present invention as the starting material.

The method of obtaining 5-hydroxypyrazoles compounds represented by formula (1)is not particularly limited. In other words, there may be used any method in the following examples, or any other method.

Examples of the method of synthesis

With respect to the method of synthesis of 5-hydroxypyrazoles compounds can be mentioned as an example of Hiroshi Yamanaka et al., Hetero-Kan Kagobotsu no Called (the Chemistry of heterocyclic compounds). Chapter 5, Kodansha Scientific (1988) and J.A.Joule and K.Mills, Handbook of Heterocyclic Chemistry (heterocyclic soy is inanim). 2-nd edition. Chapter 4.3.2.3, Pergamon (2000).

For example, the carrying out of the reaction of β-keto-ester compounds with hydrazine powered connection and, more specifically, the way in which can be synthesized 1-methyl-5-hydroxy-3-cryptomaterial exit 49% by boiling under reflux ethyl-4,4,4-triftoratsetata and methylhydrazine with a water solvent by heating for 2 hours, published in the Journal of Heterocyclic Chemistry, Vol.27, 243 (1990).

Similarly, the method of conducting the reaction diapir oxaloacetic acid with hydrazine powered connection, resulting in a gain of 3-(alkoxycarbonyl)-5-hydroxypyrazoles connection, and a way of turning alkoxycarbonyl group in the resulting compound in a cyanic group is described in detail in Kokai (publication of the application for which has not been done) No. 10-287654.

Similarly, the method of obtaining 3-cyano-5-hydroxypyrazoles compounds by the reaction of α-cunoasterea acid diazonium salt described in Kokoku publication of the application, an examined) No. 51-33556.

Deputy R1

For formula (1)representing 5-hydroxypyrazoles compound which is a starting compound in the method of the present invention, examples of the substituent denoted by the symbol R1in the formula (1)include the following:

(1) a hydrogen atom;

(2) a linear or branched C1-is 6-alkyl group with the number of carbon atoms from 1 to 6 (hereinafter, with regard to the number of carbon atoms, for example, when the number of carbon atoms is from 1 to 6, will simply use the notation "C1-C6"), such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, sec-bucilina group, tert-bucilina group, n-pencilina group and n-exilda group;

(3) an aromatic hydrocarbon group, a monocyclic or condensed rings, including forming the ring atoms of from 6 to 14, mostly from 6 to 10, such as a phenyl group or naftalina group; and aromatic hydrocarbon group may have one or more substituents, such as groups shown below in (3.1)-(3.21):

(3.1) a halogen atom, such as bromine, chlorine, fluorine and iodine

(3.2) a linear or branched C1-C6-alkyl group such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, sec-bucilina group, tert-bucilina group, n-pencilina group and n-exilda group,

(3.3) a hydroxyl group,

(3.4) a linear or branched C1-C6-alkoxy group such as methoxy group, ethoxy group, n-propoxy group, isopropoxy-group

(3.5) a linear or branched C1-C6-hydroxyalkyl group, such as hydroxymethylene group and 1-hydroxyethylene group,

(3.6) the linear or Svetlana (C1-C6-alkoxy)-(C1-C6-alkyl) group, such as methoxymethyl group, 1-ethoxyethylene group and 1-ethoxyethylene group,

(3.7) a linear or branched C1-C6-halogenation group, such as permetrina group, deformational group and triptorelin group,

(3.8) a carboxyl group,

(3.9) salt of carboxyl group with a metal, introducing alkali metal salt such as sodium salt, potassium salt, lithium salt, and alkali earth metal salt such as calcium salt, barium salt and a magnesium salt,

(3.10) a linear or branched (C1-C6-alkoxy)carbonyl group, such as methoxycarbonyl group and ethoxycarbonyl group,

(3.11) arylcarbamoyl group with those forming the ring atoms of from 6 to 14, mostly from 6 to 10, such as benzoline group and napolina group,

(3.12) heteroarylboronic group, monocyclic or condensed ring having from 1 to 4 heteroatoms selected from the group comprising a nitrogen atom, an oxygen atom and a sulfur atom, with the number forming the ring atoms from 5 to 14, mostly from 5 to 10, such as pyridylcarbonyl group, taylorsville group and forelornly group,

(3.13) the nitro-group,

(3.14) amino group,

(3.15) a linear or branched mono - or di(C1-C6-alkyl)amino group, such as methylaminopropyl, dimethylamine the group, atramentaria and diethylaminopropyl,

(3.16) a linear or branched (C1-C6-alkyl)carbylamine, such as acetylamino, propionamidoxime and bucillamine,

(3.17) a linear or branched hydroxycarbonyl-(C1-C6-alkyl)group, such as hydroxycarbonylmethyl group and 1-hydroxycarbonylmethyl group,

(3.18) a linear or branched (C1-C6-alkoxy)carbonyl-(C1-C6-alkyl) group, such as methoxycarbonylmethylene group and 1-ethoxycarbonylmethylene group,

(3.19) a linear or branched aminocarbonyl-(C1-C6-alkyl) group, such as aminocarbonyl(C1-C6-alkyl) group such as aminocarbonylmethyl group and 1-aminocarbonylmethyl group,

(3.20) a linear or branched (C1-C6-alkyl)aminocarbonyl-(C1-C6-alkyl) group, such as metilaminoantipirina group, 1-metilaminopropionitrila group and 1-etilamingidrokhlorida group and

(3.21) cyano;

(4) an aromatic heterocyclic group, a monocyclic or condensed ring having from 1 to 4 heteroatoms, which are selected from the group comprising a nitrogen atom, an oxygen atom and a sulfur atom, with the number forming the ring atoms from 5 to 14, mostly from 5 to 10, which are, for example, furilla group, benzoperylene group, Peregrina group, thienyl group, benzocain is supplemented flax group, oxazolidine group, benzoxazolyl group, thiazolidine group, benzothiazolyl group, isooxazolyl group, perazella group, pyrimidinyl group, indayla group, hyalinella group, pyrazolidine group, imidazolidinyl group, benzimidazolyl group, thiazolidine group and trainline group; and aromatic heterocyclic group may have one or more substituents, such as groups shown below in (4.1)-(4.19):

(4.1) a linear or branched C1-C6-alkyl group such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, sec-bucilina group, tert-bucilina group, n-pencilina group and n-exilda group,

(4.2) a hydroxyl group,

(4.3) linear or branched C1-C6-alkoxy group such as methoxy group, ethoxy group, n-propoxy group, isopropoxy-group

(4.4) a linear or branched C1-C6-hydroxyalkyl group, such as hydroxymethylene group and 1-hydroxyethylene group,

(4.5) a linear or branched (C1-C6-alkoxy)-(C1-C6-alkyl) group, such as methoxymethyl group, ethoxyethylene group and ethoxyethylene group,

(4.6) a linear or branched C1-C6-halogenation group, such as permetrina group, deformational group and triptoreline gr is the PAP

(4.7) a carboxyl group,

(4.8) salt of carboxyl group with a metal, introducing alkali metal salt such as sodium salt, potassium salt, lithium salt, and alkali earth metal salt such as calcium salt, barium salt and a magnesium salt,

(4.9) a linear or branched (C1-C6-alkoxy)carbonyl group, such as methoxycarbonyl group and ethoxycarbonyl group,

(4.10) a halogen atom, such as bromine, chlorine, fluorine and iodine

(4.11) the nitro-group,

(4.12) amino group,

(4.13) a linear or branched mono - or di(C1-C6-alkyl)amino group, such as methylaminopropyl, dimethylaminopropyl, atramentaria and diethylaminopropyl,

(4.14) a linear or branched (C1-C6-alkyl)carbylamine, such as acetylamino, propionamidoxime and bucillamine,

(4.15) cyano,

(4.16) formyl group,

(4.17) a linear or branched (C1-C6-alkyl)carbonyl group, such as methylcarbamyl group and acylcarnitine group,

(4.18) arylcarbamoyl group with those forming the ring atoms of from 6 to 14, mostly from 6 to 10, such as benzoline group and napolina group, and

(4.19) heteroarylboronic group, monocyclic or condensed ring having from 1 to 4 heteroatoms, which are selected from the group comprising an atom of the azo is a, an oxygen atom and a sulfur atom, with the number forming the ring atoms from 5 to 14, mostly from 5 to 10, such as pyridylcarbonyl group, taylorsville group and forelornly group,

(5) non-aromatic heterocyclic group, a monocyclic or condensed ring having from 1 to 4 heteroatoms, which are selected from the group comprising a nitrogen atom, an oxygen atom and a sulfur atom, with the number forming the ring atoms from 5 to 14, mostly from 5 to 10, which are, for example, hydroporinae group, Pernilla group, tyrannina group, Taanilinna group, pyrrolidinyl group, indolinyl group, piperidinyl group, imidazolidinyl group and piperazinilnom group; and non-aromatic heterocyclic group may have one or more substituents, such as groups, below in (5.1)-(5.19):

(5.1) a linear or branched C1-C6-alkyl group such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, sec-bucilina group, tert-bucilina group, n-pencilina group and n-exilda group,

(5.2) a hydroxyl group,

(5.3) a linear or branched C1-C6-alkoxy group such as methoxy group, ethoxy group, n-propoxy group, isopropoxy-group

(5.4) a linear or branched C1-Cherokeecasino group, such as hydroxymethylene group and hydroxyethylene group,

(5.5) a linear or branched (C1-C6-alkoxy)-(C1-C6-alkyl) group, such as methoxymethyl group, ethoxyethylene group and ethoxyethylene group,

(5.6) a linear or branched C1-C6-halogenation group, such as permetrina group, deformational group and triptorelin group,

(5.7) a carboxyl group,

(5.8) salt of carboxyl group with a metal, introducing alkali metal salt such as sodium salt, potassium salt, lithium salt, and alkali earth metal salt such as calcium salt, barium salt and a magnesium salt,

(5.9) a linear or branched (C1-C6-alkoxy)carbonyl group such as methoxycarbonyl group and ethoxycarbonyl group,

(5.10) a halogen atom, such as bromine, chlorine, fluorine and iodine

(5.11) the nitro-group,

(5.12) amino group,

(5.13) a linear or branched mono - or di(C1-C6-alkyl)amino group, such as methylaminopropyl, dimethylaminopropyl, atramentaria and diethylaminopropyl,

(5.14) a linear or branched (C1-C6-alkyl)carbylamine such as acetylamino, propionamidoxime and bucillamine,

(5.15) cyano,

(5.16) formyl group,

(5.17) a linear or branched (C1-C6-alkyl)carbonyl group, such as methylcarbamyl the group and acylcarnitine group,

(5.18) arylcarbamoyl group with those forming the ring atoms of from 6 to 14, mostly from 6 to 10, such as benzoline group and napolina group, and

(5.19) heteroarylboronic group, monocyclic or condensed ring having from 1 to 4 heteroatoms, which are selected from the group comprising a nitrogen atom, an oxygen atom and a sulfur atom, with the number forming the ring atoms from 5 to 14, mostly from 5 to 10, such as pyridylcarbonyl group, taylorsville group and forelornly group.

Preferred substituent R1

From the standpoint of easy availability of the above substituents suitable for use as substituents R1are the following.

Preferred C1-C6-alkyl group, a representative of which is the methyl and aromatic hydrocarbon group with the number forming the ring atoms of from 6 to 14, representing phenyl, and methyl group and phenyl group are preferable.

Electron-withdrawing group, R2

Electron-withdrawing group represented by the formula (1) symbol R2that means an atomic group capable to pull an electron from another part due to the inductive effect, and such an atomic group is an aromatic hydrocarbon group ilizhe such an atomic group is an aromatic heterocyclic group. Among the specific examples of electron-withdrawing group, R2includes the following groups:

(1) linear or branched C1-C6-halogenation group, such as deformational group and triptorelin group; carboxyl group or salt of the carboxyl group with a metal, introducing alkali metal salt such as sodium salt, potassium salt, lithium salt, and alkali earth metal salt such as calcium salt, barium salt and magnesium salt;

(2) linear or branched (C1-C6-alkoxy)carbonyl group, such as methoxycarbonyl group and ethoxycarbonyl group;

(3) a halogen atom, such as bromine, chlorine, fluorine and iodine; nitro-group; formyl group;

(4) a linear or branched (C1-C6-alkyl)carbonyl group, such as methylcarbamyl group (acetyl group) and acylcarnitine group;

(5) arylcarbamoyl group with those forming the ring atoms of from 6 to 14, mostly from 6 to 10, such as benzoline group and napolina group;

(6) heteroarylboronic group, monocyclic or condensed ring having from 1 to 4 heteroatoms, which are selected from the group comprising a nitrogen atom, an oxygen atom and a sulfur atom, with the number forming the ring atoms from 5 to 14, mostly from 5 to 10, such as pyridylcarbonyl group, Tieni the carbonyl group and forelornly group;

(7) aminocarbonyl group, linear or branched mono - or di(C1-C6-alkyl)aminocarbonyl group, such methylaminomethyl group and dimethylaminocarbonylmethyl group; cyano;

(8) an aromatic hydrocarbon group containing as a substituent one or more atomic groups able to pull an electron from another part due to the inductive effect, with those forming the ring atoms of from 6 to 14, mostly from 6 to 10, such as clorfenamina group (for example, 2,4-dichlorophenyl), carboxyaniline group and nitroaniline group; and

(9) a heterocyclic group, a monocyclic or condensed ring containing as a substituent one or more atomic groups able to pull an electron from another part due to the inductive effect, and with up to 1 to 4 heteroatoms, which are selected from the group comprising a nitrogen atom, an oxygen atom and a sulfur atom, with the number forming the ring atoms from 5 to 14, mostly from 5 to 10, such as clorfenamina group, chlorobenzophenone group, chloropyridine group, chloraniline group, carboxybenzoyl group, nitroacetanilide group, cyanobacteria group, hartmanella group, chlorobenzothiazole group, acetylthiocholine group, benzoimidazolyl group, chloropyrazole the group, chloropyrimidine group, floridalma group, hlorhinaldola group, aminocarbonylmethyl group, metilaminopropionitrila group, triftoratsetofenona group, methoxycarbonylmethyl group and chlortrianisene group.

Preferred electron-withdrawing group, R2

From the point of view of stability under the reaction conditions, i.e. in the presence of a base, and the ultimate stability of the output from the above-described electron-withdrawing groups R2preferably used are the following:

preferred C1-C6-halogenation group, representative of which is trifluoromethyl; an aromatic hydrocarbon group containing as a substituent one or more atomic groups able to pull an electron from another part due to the inductive effect, with those forming the ring atoms of from 6 to 14, which is 2,4-dichlorophenyl; and cyano; and most preferred triptorelin group, 2,4-dichlorophenyl, and cyano.

Preferred 5-hydroxypyrazoles connection

Accordingly, specific examples of 5-hydroxypyrazoles compounds represented by formula 1 include 5-hydroxy-3-cryptomaterial, 3-etoxycarbonyl-5-hydroxypyrazol, 3-acetyl-5-hydroxypyrazol, 3-benzoyl-5-hydroxypyrazol, 5-g is droxy-3-(3-pyridylcarbonyl)pyrazole, 3-cyano-5-hydroxypyrazol, 5-hydroxy-1-methyl-3-cryptomaterial, 3-etoxycarbonyl-5-hydroxy-1-methylpyrazole, 3-chloro-5-hydroxy-1-methylpyrazole, 5-hydroxy-1-methyl-3-nitropyrazole, 5-hydroxy-1-methyl-3-(2-thienylboronic)pyrazole, 5-hydroxy-1-methyl-3-(3-pyridylcarbonyl)pyrazole, 3-dimethylaminoethyl-5-hydroxy-1-the methylpyrazole, 5-hydroxy-1-methyl-3-(4-triptoreline)pyrazole, 3-(4-ethoxycarbonylphenyl)-5-hydroxy-1-methylpyrazole, 3-(2,4-dichlorophenyl)-5-hydroxy-1-methylpyrazole, 3-(3,5-dinitrophenyl)-5-hydroxy-1-methylpyrazole, 3-(4-dimethylaminobenzoyl)-5-hydroxy-1-methylphenylazo, 5-hydroxy-1-n-propyl-3-cryptomaterial, 3-cyano-1-n-hexyl-5-hydroxypyrazol, 1-tert-butyl-5-hydroxy-3-cryptomaterial, 1-tert-butyl-3-(4-shikoba)-5-hydroxypyrazol, 3-(4-acetylphenyl)-tert-butyl-5-hydroxypyrazol, 1-tert-butyl-3-(4-cyanophenyl)-5-hydroxypyrazol, 5-hydroxy-1-phenyl-3-cryptomaterial, 3-cyano-5-hydroxy-1-phenylpyrazol, 1-(4-chlorophenyl)-3-etoxycarbonyl-5-hydroxypyrazol, 3-etoxycarbonyl-5-hydroxy-1-(2-were)pyrazole, 3-etoxycarbonyl-5-hydroxy-1-(2-methoxymethyl)pyrazole, 1-(4-acetylphenyl)-3-etoxycarbonyl-5-hydroxypyrazol, 3-etoxycarbonyl-5-hydroxy-1-(3-nitrophenyl)pyrazole, 5-hydroxy-1-(2-methoxyphenyl)-3-cryptomaterial, 5-hydroxy-3-trifluoromethyl-1-(4-triptoreline)pyrazole, 1-(4-ethoxycarbonylphenyl)-5-hydroxy-3-cryptomailer is, 1-(4-dimethylaminophenyl)-5-hydroxy-3-cryptomaterial, 1-(4-acetamidophenyl)-5-hydroxy-3-cryptomaterial, 1-(4-methoxycarbonylmethylene)-cryptomaterial, 1-(4-dimethylaminocarbonylmethyl)-5-hydroxy-3-cryptomaterial, 1-(4-cyanophenyl)-5-hydroxy-3-cryptomaterial, 1-(2-naphthyl)-5-hydroxy-3-cryptomaterial, 1-(2-benzothiazolyl)-5-hydroxy-3-cryptomaterial, 5-hydroxy-1-(2-pyridyl)-3-cryptomaterial and 5-hydroxy-1-(2-pyrimidyl)-3-cryptomaterial.

Sulfur compound

The following describes the sulfur compound represented by the formula (2).

Among the examples of the substituent represented by the symbol R3in the formula (2)include the following:

(1) linear or branched C1-C6-alkyl group such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, sec-bucilina group, tert-bucilina group, n-pencilina group and n-exilda group; aromatic hydrocarbon group, a monocyclic or condensed rings, including forming the ring atoms of from 6 to 14, mostly from 6 to 10, such as a phenyl group or naftalina group (aromatic hydrocarbon group can have one or more substituents, for example linear or branched C1-C6-alkyl group such as methyl group, ethyl group, n-p is opalina group, ISO-propyl group, n-bucilina group, sec-bucilina group, tert-bucilina group, n-pencilina group and n-exilda group),

(2) a hydroxyl group,

(3) a linear or branched C1-C6-alkoxy group such as methoxy group, ethoxy group, n-propoxy group, isopropoxy-group

(4) a linear or branched C1-C6-hydroxyalkyl group, such as hydroxymethylene group and hydroxyethylene group,

(5) a linear or branched (C1-C6-alkoxy)-(C1-C6-alkyl) group, such as methoxymethyl group, ethoxyethylene group and ethoxyethylene group,

(6) a linear or branched C1-C6-halogenation group, such as permetrina group, deformational group and triptorelin group; carboxyl group, salt of carboxyl group with a metal, introducing alkali metal salt such as sodium salt, potassium salt, lithium salt, and alkali earth metal salt such as calcium salt, barium salt and a magnesium salt,

(7) a linear or branched (C1-C6-alkoxy)carbonyl group, such as methoxycarbonyl group and ethoxycarbonyl group,

(8) a halogen atom, such as bromine, chlorine, fluorine and iodine; nitro-group and the amino group,

(9) linear or branched mono - or di(C1-C6-alkyl)amino group, such as methylaminopropyl, dimethylaminopropyl, who filamentgroup and diethylaminopropyl,

(10) linear or branched (C1-C6-alkyl)carbylamine, such as acetylamino, propionamidoxime and bucillamine; a cyano group, formyl group,

(11) linear or branched (C1-C6-alkyl)carbonyl group, such as methylcarbamyl group and acylcarnitine group,

(12) arylcarbamoyl group with those forming the ring atoms of from 6 to 14, mostly from 6 to 10, such as benzoline group and napolina group, and

(13) heteroarylboronic group, monocyclic or condensed ring having from 1 to 4 heteroatoms, which are selected from the group comprising a nitrogen atom, an oxygen atom and a sulfur atom, with the number forming the ring atoms from 5 to 14, mostly from 5 to 10, such as pyridylcarbonyl group, taylorsville group and forelornly group, and

(14) an aromatic or non-aromatic heterocyclic group include monocyclic aromatic group or an aromatic group with condensed rings, having from 1 to 4 heteroatoms, which are selected from the group comprising a nitrogen atom, an oxygen atom and a sulfur atom, with the number forming the ring atoms from 5 to 14, mostly from 5 to 10, which are, for example, furilla group, benzoperylene group, Peregrina group, thienyl group, benzothiazoline the group, oxazolidine group, thiadiazolyl group, perazella group, pyrimidinyl group, indayla group, hyalinella group, pyrazolidine group, imidazolidinyl group, benzimidazolyl group, thiazolidine group and trainline group; an aromatic heterocyclic group may have one or more substituents, for example linear or branched C1-C6-alkyl group, such as metal group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, sec-bucilina group, tert-bucilina group, n-pencilina group and n-exilda group,

(15) a hydroxyl group,

(16) a linear or branched C1-C6-alkoxy group such as methoxy group, ethoxy group, n-propoxy group, isopropoxy-group

(17) a linear or branched C1-C6-hydroxyalkyl group, such as hydroxymethylene group and hydroxyethylene group,

(18) a linear or branched (C1-C6-alkoxy)-(C1-C6-alkyl) group, such as methoxymethyl group, ethoxyethylene group and ethoxyethylene group,

(19) a linear or branched C1-C6-halogenation group, such as permetrina group, deformational group and triptorelin group,

(20) a carboxyl group or salt of the carboxyl group with a metal, introducing the alkali metal salt, such as on rieva salt, potassium salt, lithium salt, and alkali earth metal salt such as calcium salt, barium salt and a magnesium salt,

(21) a linear or branched (C1-C6-alkoxy)carbonyl group, such as methoxycarbonyl group and ethoxycarbonyl group,

(22) a halogen atom, such as bromine, chlorine, fluorine and iodine; nitro-group and the amino group,

(23) a linear or branched mono - or di(C1-C6-alkyl)amino group, such as methylaminopropyl, dimethylaminopropyl, atramentaria and diethylaminopropyl,

(24) a linear or branched (C1-C6-alkyl)carbylamine, such as acetylamino, propionamidoxime and bucillamine; a cyano group, formyl group,

(25) a linear or branched (C1-C6-alkyl)carbonyl group, such as methylcarbamyl group and acylcarnitine group,

(26) arylcarbamoyl group with those forming the ring atoms of from 6 to 14, mostly from 6 to 10, such as benzoline group and napolina group, and

(27) heteroarylboronic group, monocyclic or condensed ring having from 1 to 4 heteroatoms, which are selected from the group comprising a nitrogen atom, an oxygen atom and a sulfur atom, with the number forming the ring atoms from 5 to 14, mostly from 5 to 10, such as pyridylcarbonyl group, taylorsville group, fullcarbon the other group and non-aromatic heterocyclic group, monocyclic or condensed ring having from 1 to 4 heteroatoms, which are selected from the group comprising a nitrogen atom, an oxygen atom and a sulfur atom, with the number forming the ring atoms from 5 to 14, mostly from 5 to 10, which are, for example, hydroporinae group, Pernilla group, tiarella group, Taanilinna group, pyrrolidinyl group, indolinyl group, piperidinyl group, imidazolidinyl group and piperazinilnom group (nonaromatic heterocyclic group may have one or more substituents, for example linear or branched C1-C6-alkyl group, such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, sec-bucilina group, tert-bucilina group, n-pencilina group and n-exilda group) and a hydroxyl group,

(28) a linear or branched C1-C6-alkoxy group such as methoxy group, ethoxy group, n-propoxy group, isopropoxy-group

(29) a linear or branched C1-C6-hydroxyalkyl group, such as hydroxymethylene group and hydroxyethylene group,

(a) a linear or branched (C1-C6-alkoxy)-(C1-C6-alkyl) group, such as methoxymethyl group, ethoxyethylene group and ethoxyethylene group,

(30) a linear or branched C1-C6-halogenation the group, such as permetrina group, deformational group and triptorelin group; carboxyl group, salt of carboxyl group with a metal, introducing alkali metal salt such as sodium salt, potassium salt, lithium salt, and alkali earth metal salt such as calcium salt, barium salt and a magnesium salt,

(31) a linear or branched (C1-C6-alkoxy)carbonyl group, such as methoxycarbonyl group and ethoxycarbonyl group,

(32) a halogen atom, such as bromine, chlorine, fluorine and iodine; nitro-group and the amino group,

(33) a linear or branched mono - or di(C1-C6-alkyl)amino group, such as methylaminopropyl, dimethylaminopropyl, atramentaria and diethylaminopropyl,

(34) a linear or branched (C1-C6-alkyl)carbylamine, such as acetylamino, propionamidoxime and bucillamine; a cyano group, formyl group,

(35) linear or branched (C1-C6-alkyl)carbonyl group, such as methylcarbamyl group and acylcarnitine group,

(36) arylcarbamoyl group with those forming the ring atoms of from 6 to 14, mostly from 6 to 10, such as benzoline group and napolina group, and

(37) heteroarylboronic group, monocyclic or condensed ring having from 1 to 4 heteroatoms which are selected from gr is PPI, which includes the nitrogen atom, oxygen atom and sulfur atom, with the number forming the ring atoms from 5 to 14, mostly from 5 to 10, such as pyridylcarbonyl group, taylorsville group and forelornly group.

Group X

X in the formula (2) is, for example, a hydrogen atom or a metal atom which is represented, for example, alkali metal such as sodium, potassium and lithium, and alkaline earth metal such as magnesium and calcium.

In the case when n in the formula (2) is 0, the compound is a thiol or its salt, and when n is 2, the connection is sulfinol acid or its salt.

In intended for use in the reaction of sulfur compound represented by the formula (2), X can be a hydrogen or alkali metal salt, such as sodium, potassium and lithium, or alkaline earth salt of a metal, such as magnesium and calcium. In addition, in the case when the sulfur compound is a thiol (compound of formula (2) with n equal to 0), the precursor from which you can get a thiol and a representative of which is isothiouronium salt or a similar compound, is easily obtained by reaction of the corresponding alkylhalogenide with thiourea, can be hydrolyzed in the same reaction apparatus, so that the system can be obtained and used IP is odny material to obtain thiol.

A specific example sulfur compounds

Accordingly, the specific examples of sulfur compounds represented by formula (2)include thiamethoxam sodium, titoxd sodium, 2-Tibetan, thiophenol, 2-ethylthiophene, 4-methoxythiophene, 4-chlorothiophenol, 4-nitrothiophene, 4-dimethylaminophenol, 4-cyanothiophene, 4-acetylthiophene, 2-mercaptopyridine, 2-mercaptobenzothiazoles, isothiouronium salt, representatives of which are the hydrochloride of n-hexyltrichlorosilane, hydrochloride of benzoylthiocarbamide and hydrochloride [5,5-dimethyl(4,5-dihydroisoxazole-3-yl)]thiocarboxamides, bansilalpet sodium and p-toluensulfonate sodium.

The carrying out of the reaction

Here's how the reaction of 5-hydroxypyrazoles compounds represented by formula (1), with a sulfur compound represented by the formula (2), resulting in a gain of 5-hydroxy-4-dimethylpyrazole compound represented by the formula (3).

Formaldehyde

The above reaction is carried out in the presence of formaldehyde. Form of formaldehyde used in this reaction is not particularly limited, and formaldehyde can be used in any form, however, convenient for work and it is preferable to use an aqueous solution of formaldehyde at a concentration of from 35 to 50%, for example, readily available commercial is a mini 35%formalin or paraformaldehyde (polymer of formaldehyde, which forms in the system of formaldehyde as a result of hydrolysis and, therefore, can be used as the equivalent of formaldehyde).

The used amount of

The amount of formaldehyde used may be sufficient, per equivalent of the starting compound represented by the formula (1), but usually the amount is from 1.0 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents per 1 mol of starting compound represented by the formula (1).

The used amount of sulfur compounds represented by formula (1)may be sufficient if it is equivalent or more than equivalent, based on the original compound of formula (1), but the amount used is from 1.0 to 2.0 equivalents, preferably from 1.0 to 1.2 equivalent per 1 mol of starting compound represented by the formula (1).

Base

In the present invention the reaction is carried out in the presence of a base. Examples of the base used in the reaction include the following reasons:

(1) alkali metal hydride such as sodium hydride, potassium hydride and lithium hydride;

(2) alkali metal such as metallic sodium, metallic potassium and metallic lithium;

(3) the alkali metal hydroxide, such as sodium hydroxide, the hydroxide is Aliya and lithium hydroxide;

(4) the alkali earth metal hydroxide such as barium hydroxide, magnesium hydroxide and calcium hydroxide;

(5) a carbonate of an alkali metal such as sodium carbonate, potassium carbonate; sodium bicarbonate and potassium bicarbonate;

(6) an inorganic base which is represented, for example, the oxide of the alkali earth metal such as barium oxide, magnesium oxide and calcium oxide; and a metal alkoxide such as sodium methoxide, ethoxide sodium, potassium methoxide, ethoxide potassium tert-piperonyl potassium; and

(7) inorganic base which is represented, for example, alkaline metal, such as utility.

Of these compounds, the alkali metal hydroxide and a metal alkoxide are preferred because of their availability, and the most preferred of these, the alkali metal hydroxide, in particular sodium hydroxide, since the reaction can be carried out with the aqueous solvent and, consequently, it is possible to reduce such a cumbersome operation, as the purification of waste water.

The amount used of the base

Can be used any number of reasons, which is sufficient for satisfactory reaction, but that the amount used is, for example, from 1.0 to 20 mol, preferably from 1.5 to 10 mol and more preferably from 1.5 to 3.0 mol per mol 5-hydroxylating connection (parent compound), represented by formula (1).

Solvent

The reaction of the present invention can, if desired, be carried out in the presence of a solvent.

Used in the reaction solvent may be satisfactory if it does not inhibit the reaction, and examples include water; alcohols such as methanol and ethanol; aromatic hydrocarbons such as toluene, xylene and chlorobenzene; halogenated aliphatic hydrocarbons such as dichloromethane and chloroform; aprotic polar solvents such as dimethylformamide, dimethylacetamide, n-organic, tetramethylrhodamine, hexamethylphosphorotriamide (NMRA) and propylene carbonate; compounds with ethers, such as diethyl ether, tetrahydrofuran and dioxane; aliphatic hydrocarbons such as pentane and n-hexane. These solvents can be used individually or as a mixed solvent with an arbitrary ratio of the mixture components. From the viewpoint of solubility and reactivity of the Foundation of the reaction is preferably conducted using water or alcohols, and more preferably in water or methanol.

The amount of solvent may be sufficient if it allows a satisfactory way to stir the reaction system, but generally this amount is from 0.05 to 10 l and preferably is t 0.5 to 2 liters per 1 mol of 5-hydroxypyrazoles connection (parent compound), represented by formula (1).

Reaction conditions

The temperature of this reaction can vary, for example, from 0°C to the boiling point of the used solvent, but mostly the reaction is carried out at a temperature of from 20 to 50°C., in particular at room temperature, applying a hashing because it is easy to implement and leads to high output.

Discuss the reaction is not particularly limited, but usually, the reaction can be satisfactorily completed within time 1 to 10 hours.

According to this reaction, 5-hydroxy-4-dimethylpyrazole compound represented by the formula (3)can be obtained with high yield and easy by under mild conditions. The resulting 5-hydroxy-4-dimethylpyrazole compound represented by the formula (3), is a compound used as an intermediate product in the manufacture of pharmaceutical and agricultural chemical products.

EXAMPLES

The method of obtaining the compounds of the present invention are described below based on examples, but the invention is not limited to these examples.

Reference example 1

Synthesis of 5-hydroxy-1-methyl-3-cryptomaterial

Ethyl-4,4,4-triftoratsetata (of 92.1 g, 0.5 mol) is dissolved in 60.1 g (1.0 mol) of acetic acid. The resulting solution is cooled to 10°C or below p and stirring, and added thereto dropwise over 1 hour 65.8 g (0.5 mol) of 35%aqueous solution of methylhydrazine. After adding dropwise, the solution stirred for 1 hour at room temperature and then 5 hours at 80°C. After completion of the reaction, the reaction solution is cooled to room temperature and add 150 ml of toluene and 600 ml of water and 48 g (1.2 mol) of sodium hydroxide. After separation of the liquid to the obtained aqueous layer was added dropwise 154 g (1.4 mol) of 35%hydrochloric acid and collected by filtration the resulting crystals. The crystals are washed twice with 50 ml water and dried in a hot-air dryer, receiving 71,8 g (yield 86,5%) target compound as pale yellow crystals.

LC-MS (EI) (hromas spectrometry with electron ionization): m/z=166 (M+), TPL 179-180°C.

Reference example 2

Synthesis of 5-hydroxy-1-phenyl-3-cryptomaterial

Ethyl-4,4,4-triftoratsetata (of 18.4 g, 0.1 mol) is dissolved in 12.0 g (0.2 mol) of acetic acid. The resulting solution is cooled to 10°C. or below with stirring and added to it dropwise over 0.5 hours to 11.8 g (0.11 mol) of phenylhydrazine. After adding dropwise, the solution stirred for 1 hour at room temperature and then 5 hours at 80°C. After completion of the reaction, the reaction solution is cooled to room temperature and add 100 ml of water. The resulting crystals are collected by filtration, washed twice with 50 ml water and dried in hot-air drying is e, getting to 22.3 g (yield 98,0%) target compound as pale yellow crystals.

LC-MS (EI): m/z=228 (M+), TPL 190-192°C.

Reference example 3

Synthesis of the hydrochloride of 5-hydroxy-3-cryptomaterial

Ethyl-4,4,4-triftoratsetata (of 18.4 g, 0.1 mol) was dissolved in 20 ml of ethanol. The resulting solution is cooled to 10°C. or below with stirring and added to it dropwise over 0.5 hours 6.0 g (0.12 mol) of hydrazine. After adding dropwise, the solution stirred for 1 hour at room temperature and then 5 hours at boiling point. After completion of the reaction, the reaction solution is cooled to room temperature and add 100 ml of water and 20.6 g (0.2 mol) of 35%hydrochloric acid. The resulting crystals are collected by filtration, washed twice with 10 ml water and dried in a hot-air dryer, receiving 12.8 g (yield 68,1%) target compound as white crystals.

LC-MS (EI): m/z=152 (M+).

Reference example 4

Synthesis of 3-etoxycarbonyl-5-hydroxy-1-methylpyrazole

Monosodium salt of diethylaminoacetate (50.0 g, 0.24 mol) is suspended in 500 ml of ethanol and add 25 ml of acetic acid. Then for 0.5 hour and added dropwise with stirring, 15 g (0.33 mol) of 97%methylhydrazine. After adding dropwise, the solution stirred for 1 hour at room temperature and then 5 hours at a temperature of boil is. The resulting solution is cooled, remove the ethanol by distillation under reduced pressure and add to the residue 200 ml of ethyl acetate and 100 ml of water. After separation of the liquid obtained aqueous layer was re-extracted with 50 ml ethyl acetate and the combined an ethyl acetate layer was washed with 50 ml of water and then 50 ml of saturated salt solution. Received an ethyl acetate layer is dried over anhydrous sodium sulfate and remove the solvent by distillation under reduced pressure. Once added to the precipitated crystals 100 ml of water crystals are collected by filtration, washed twice with 10 ml water and dried in a hot-air dryer, receiving 29,2 g (yield 71,8%) target compound as pale yellow crystals.

LC-MS (EI): m/z=170 (M+), 125 (base), TPL 151°C.

Reference example 5

Synthesis of 3-cyano-5-hydroxy-1-phenylpyrazole

To 5.6 g (0.06 mol) of aniline add water (120 ml) and 15 ml of 35%hydrochloric acid and dissolve the mixture. Then added dropwise 24 ml of water with dissolved 4,2 g (0.06 mol) of sodium nitrite with stirring and ice cooling to 0-5°C. the resulting solution was stirred for 1 hour to obtain chloride benzodiapine. An aqueous solution of this diazonium salt is added dropwise to 120 ml of pyridine solution containing 10.2 g (0.06 mol) diethyl-α-cyanoacrylate, with stirring and cooling the ice. After adding dropwise, the solution stirred for 1 hour with ice cooling and then for 1 hour at room temperature. After completion of the reaction, add 240 ml of 2%aqueous sodium hydroxide solution and then stirred for 2 hours. The resulting reaction solution was added dropwise to 240 ml of 35%hydrochloric acid under ice cooling, is collected by filtering the precipitated crystals, washed with 10 ml of water and dried in a hot-air dryer, receiving of 8.4 g of the crude crystals of the target compound in the form of red-brown crystals. The crude crystals are recrystallized from a mixture of diethyl ether/petroleum ether and dried in a hot-air dryer, gaining 5.7 g (yield 51,3%) target compound as pale yellow crystals.

LC-MS (EI): m/z=185 (M+), 125 (base), TPL 190°C.

Reference example 6

Synthesis of 3-(2,4-dichlorophenyl)-5-hydroxy-1-methylpyrazole

Ethylmalonate potassium (22.1 g, 0.13 mol) is suspended in 200 ml of ethyl acetate, then with stirring and ice cooling is added to the suspension sequentially 29,14 g (0.29 mol) of triethylamine and 13.7 g (0.14 mol) of magnesium chloride. The obtained suspension liquid is stirred for 6 hours at 40°C, again cooled with ice for 1 hour and added dropwise to 20.9 g (0.1 mol) of 2,4-dichlorobenzotrifluoride, maintaining the temperature of the reaction solution at °C or below. After adding dropwise to the stirring is continued for 12 hours at room temperature. Then to the reaction solution are added dropwise 200 ml of 5%hydrochloric acid and separated the organic layer. The obtained organic layer is washed twice with 50 ml water and then 30 ml of saturated salt solution and remove the solvent by distillation under reduced pressure. To the obtained concentrated residue was added 100 ml of ethanol. The resulting solution is cooled to 10°C. or below with stirring and added to it dropwise within 1 hour of 13.1 g (0.1 mol) of 35%aqueous solution of methylhydrazine. After adding dropwise, the solution stirred for 1 hour at room temperature and then for 3 hours at 80°C. After completion of the reaction, the reaction solution is cooled to room temperature and add 300 ml of water. The resulting crystals are collected by filtration, washed twice with 50 ml water and dried in a hot-air dryer, receiving 12.3 g (yield of 50.2%) of target compound as white crystals.

1H-NMR (300 MHz, CDCl3): σ=7,53 (d, J=1.8 Hz, 1H), 7,2-7,4 (m, 2H), of 5.68 (s, 1H), 3,54 (s, 3H) ppm

LC-MS (EI): m/z=242 (M+), TPL 221-223°C.

Reference example 7

Synthesis of 3-(3,5-dinitrophenyl)-5-hydroxy-1-methylpyrazole

Ethylmalonate potassium (11,0 g, 0.07 mol) is suspended in 100 ml of ethyl acetate, after which paramasivan and and ice cooling is added to the suspension sequentially 14.5 g (to 0.19 mol) of triethylamine and 6.9 g (0.08 mol) of magnesium chloride. The obtained suspension liquid is stirred for 6 hours at 40°C, again cooled with ice for 1 hour and added dropwise to 11.5 g (0.05 mol) of 2,4-dinitrobenzonitrile, maintaining the temperature of the reaction solution at 0°C or below. After adding dropwise to the stirring is continued for 12 hours at room temperature. Then to the reaction solution are added dropwise 100 ml of 5%hydrochloric acid and separated the organic layer. The obtained organic layer is washed twice with 50 ml water and then 30 ml of saturated salt solution and remove the solvent by distillation under reduced pressure. To the obtained concentrated residue was added 100 ml of ethanol and then added dropwise at room temperature and mixing 2.4 g (0.05 mol) of 97%methylhydrazine. After adding dropwise, the solution stirred for 1 hour at room temperature and then for 3 hours at 80°C. After completion of the reaction, the reaction solution is cooled to room temperature, add 300 ml of water and collected by filtration the resulting crystals. The crystals are washed twice with 50 ml water and the resulting thereafter, the crystals are recrystallized from 50%aqueous ethanol and dried in a hot-air dryer, receiving of 4.2 g (yield 30,2%) of target compound in the form of red crystals.

1H-NMR (300 MHz, MeOH-d4): σ=8,90 (t, J=2.1 a is C, 1H), cent to 8.85 (d, J=2.1 Hz, 2H), 4,60 (s, 1H), of 3.73 (s, 3H), 3,3-3,4 (m, 1H) ppm

LC-MS (EI): m/z=264 (M+), TPL 230-231°C.

Reference example 8

Synthesis of 3-chloro-5,5-dimethyl-4,5-dihydroxyacetone

Ethanol (500 ml) and 63,0 g (0.75 mol) of sodium bicarbonate is introduced into the reaction and stirred at room temperature. After purging for 0.5 hours 84,2 g (1.50 mol) of gaseous isobutene the temperature was raised to 70°C. and the reaction solution is gradually added dropwise 131,3 g (0.5 mol) of a 40%aqueous solution of oxime dichloromaleimide isopropyl ether, and the solution was stirred at the same temperature for 8 hours. The resulting reaction solution is allowed to cool to 25°C or below, and after removal by filtration of solid inorganic substances the residue is distilled under reduced pressure (62°C/1,1 kPa), receiving and 32.3 g (51%yield) of 3-chloro-4,5-dihydroisoxazole in the form of a colorless transparent liquid.

1H-NMR (300 MHz, MeOH-d4): σ=2,88 (s, 2H), 1,41 (s, 3H) ppm

LC-MS (EI): m/z=133 (M+), 118 (base), BP. 50°C/0.7 kPa.

Reference example 9

Synthesis of hydrochloride [5,5-dimethyl(4,5-dihydroisoxazole-3-yl)]thiocarboxamide:

of 3.5%hydrochloric acid (4,17 g, 0.04 mol) are added to ethanol (100 ml, 0.51 mol) to a solution containing a 16.8 g (0.2 mol) of thiourea, and within 1 hour is added dropwise with stirring and at room temperature (26.7 g (0.2 mol) of 3-the ENT-5,5-dimethyl-4,5-dihydroisoxazole, then continue stirring at 30°C for 3 hours. Then added to the reaction solution, 100 ml of toluene. After removal of the solvent by distillation under reduced pressure precipitates of 58.3 g of white crystals. To the obtained crude crystals add 300 ml of isopropyl alcohol and heat the mixture to dissolve the crystals, and then gradually cooled, receiving a 38.5 g (yield 92,0%) target compound as white crystals.

1H-NMR (300 MHz, MeOH-d4): σ=4,84 (s, 3H), is 3.08 (s, 2H), 1,46 (s, 3H) ppm, TPL 147°C.

Example 1: Synthesis of 5-hydroxy-1-methyl-4-methylthiomethyl-3-cryptomaterial

5-Hydroxy-1-methyl-3-cryptomaterial (1.7 g, 10 mmol)synthesized in reference example 1 and 0.6 g (15 mmol) of sodium hydroxide dissolved in 10 ml of water. Stirring the resulting solution at room temperature, was added thereto dropwise 1.7 g (20 mmol) of 35%formalin solution, and then stirred for 1 hour at the same temperature. Then added dropwise at room temperature of 7.1 g (10 mol) 10%aqueous solution of timelocked sodium and the resulting mixture was stirred for 6 hours. After completion of the reaction was added to the mixture dropwise 5.0 g (50 mmol) of 35%hydrochloric acid, collected by filtration of the precipitated crystals, twice washed with 5 ml of water and dried in a hot-air dryer, receiving 1.6 g(yield 72,7%) target compound as pale yellow crystals. These crystals are recrystallized from a mixture of water-methanol, getting white crystals.

1H-NMR (300 MHz, MeOH-d4): σ=4,86 (ush., 1H), to 3.64 (s, 3H), of 3.56 (s, 2H), 2,02 (s, 2H) ppm

LC-MS (EI): m/z=226 (M+), 179 (base), TPL 123-124°C.

Example 2: Synthesis of [(5-hydroxy-1-methyl-3-cryptomaterial-4-yl)methylthio]benzene

5-Hydroxy-1-methyl-3-cryptomaterial (1.7 g, 10 mmol)synthesized in reference example 1 and 0.6 g (15 mmol) of sodium hydroxide dissolved in 10 ml of water. Stirring the resulting solution at room temperature, was added thereto dropwise 1.7 g (20 mmol) of 35%formalin solution, and then stirred for 1 hour at the same temperature. Then added dropwise at room temperature of 11.0 g (10 mol) of thiophenol and the resulting mixture was stirred for 7 hours. After completion of the reaction was added to the mixture dropwise 5.0 g (50 mmol) of 35%hydrochloric acid, collected by filtration of the precipitated crystals, twice washed with 5 ml of water and dried in a hot-air dryer, obtaining 2.2 g (yield of 76.4%) of target compound as pale yellow crystals. These crystals are recrystallized from a mixture of n-hexane/2-propanol, getting white crystals.

1H-NMR (300 MHz, MeOH-d4): σ=a 7.1 to 7.3 (m, 5H), 4,86 (ush., 1H), 3,99 (s, 3H), 3,61 (s, 3H) ppm

LC-MS (EI): m/z=288 (M+), 110 (base), TPL 152°C.

Example 3: Synthesis of 3-[(5-hydroxy-1-methyl-3-cryptomate the pyrazole-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole

5-Hydroxy-1-methyl-3-cryptomaterial (1.7 g, 10 mmol)synthesized in reference example 1 and 1.6 g (40 mmol) of sodium hydroxide dissolved in 10 ml of water. Stirring the resulting solution at room temperature, was added thereto dropwise 1.7 g (20 mmol) of 35%formalin solution, and then stirred for 1 hour at the same temperature. Then added dropwise at room temperature, 10 ml of an aqueous solution containing 2.1 g (10 mmol) of the hydrochloride [5,5-dimethyl(4,5-dihydroisoxazole-3-yl)]thiocarboxamides and the resulting mixture was stirred at the same temperature for 2 hours. After completion of the reaction was added to the mixture dropwise 5.0 g (50 mmol) of 35%hydrochloric acid, collected by filtration of the precipitated crystals, twice washed with 5 ml of water and dried in a hot-air dryer, receiving 2.5 g (yield of 80.1%) target compound as pale yellow crystals. These crystals are recrystallized from a mixture of n-hexane/2-propanol, getting white crystals.

1H-NMR (300 MHz, MeOH-d4): σ=4,88 (ush., 1H), 4,08 (s, 2H), to 3.64 (s, 3H), 2.91 in (s, 2H), 1.39 in (C, 6N) ppm

LC-MS (EI): m/z=309 (M+), 177 (base), TPL 115-116°C.

Example 4: Synthesis of 3-[(5-hydroxy-1-methyl-3-cryptomaterial-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole

5-Hydroxy-1-methyl-3-cryptomaterial (1.7 g, 10 mmol)synthesized in reference example 1 and 10 ml of 28%aqueous methane is a high solution of sodium methoxide (6.0 g, 30 mmol) dissolved in 10 ml of methanol. Stirring the resulting solution at room temperature, add 1.7 g of paraformaldehyde, and then stirred for 1 hour at the same temperature. Next, add at room temperature, 2.1 g (10 mmol) of the hydrochloride [5,5-dimethyl(4,5-dihydroisoxazole-3-yl)]thiocarboxamides and the resulting mixture was stirred for 2 hours. After completion of the reaction was added to the mixture dropwise 5.0 g (50 mmol) of 35%hydrochloric acid, add an additional 10 ml of water, collected by filtration of the precipitated crystals, twice washed with 5 ml of water and dried in a hot-air dryer, obtaining 2.6 g (yield 84,1%) target compound as pale yellow crystals.1H-NMR-spectrum is the same as in example 3.

Example 5: Synthesis of 3-[(5-hydroxy-1-methyl-3-cryptomaterial-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole

The target compound (2.3 g, yield 74,2%) was obtained as pale-yellow crystals by the same sequence of operations as in example 4, except replacing the base in the reaction of example 4 4.2 g (30 mmol) of potassium carbonate.1H-NMR-spectrum is the same as in example 3.

Example 6: (the embodiment in which the electron-withdrawing group is triptorelin group): Synthesis of 4-[(5-hydroxy-1-methyl-3-cryptomaterial-4-yl)methylsulphonyl]toluene

5-Hydroxy-methyl-3-cryptomaterial (8,3 g, 50 mmol)synthesized in reference example 1 and 3.0 g (75 mmol) of sodium hydroxide dissolved in 50 ml of water. Stirring the resulting solution at room temperature, was added thereto dropwise 8.5 g (100 mmol) of 35%formalin solution, and then stirred for 1 hour at the same temperature. Next, add at room temperature 9.0 g (50 mmol) of p-toluensulfonate sodium and the resulting mixture was stirred for 2 hours. After completion of the reaction was added to the mixture dropwise 25,0 g (250 mmol) of 35%hydrochloric acid, add an additional 100 ml of water, collected by filtration of the precipitated crystals, twice washed with 20 ml of water and dried in a hot-air dryer, receiving 14.0 g (yield 83.8 percent) of target compound as white crystals.

1H-NMR (300 MHz, MeOH-d4): σ=a 7.62 (d, J=8,4 Hz, 5H), 7,39 (d, J=8,4 Hz, 2H), 4,85 (ush., 1H), 4,32 (s, 2H), 3,63 (s, 3H), of 2.44 (s, 3H) ppm

LC-MS (EI): m/z=334 (M+), 179 (base), TPL 135°C.

Example 7: Synthesis of 4-[(5-hydroxy-1-methyl-3-cryptomaterial-4-yl)methylsulphonyl]toluene

5-Hydroxy-1-methyl-3-cryptomaterial (1.7 g, 10 mmol)synthesized in reference example 1 and 0.6 g (15 mmol) of sodium hydroxide dissolved in 10 ml of DMF. Stirring the resulting solution at room temperature, add 1.7 g of paraformaldehyde, and then stirred for 1 hour at the same temperature. Next add in on the th temperature of 1.8 g (10 mmol) of p-toluensulfonate sodium and the resulting mixture was stirred for 2 hours. After completion of the reaction was added to the mixture dropwise 5.0 g (50 mmol) of 35%hydrochloric acid, add an additional 100 ml of water, collected by filtration of the precipitated crystals, twice washed with 5 ml of water and dried in a hot-air dryer, obtaining 3.0 g (yield 88,2%) target compound as white crystals.1H-NMR-spectrum is the same as in example 6.

Example 8: Synthesis of 4-[(5-hydroxy-1-methyl-3-cryptomaterial-4-yl)methylsulphonyl]toluene

5-Hydroxy-1-methyl-3-cryptomaterial (1.7 g, 10 mmol)synthesized in reference example 1 and 0.6 g (15 mmol) of sodium hydroxide dissolved in 10 ml of toluene. Stirring the resulting solution at room temperature, add 1.7 g of paraformaldehyde, and then stirred for 24 hours at the same temperature. Next, add at room temperature, 1.8 g (10 mmol) of p-toluensulfonate sodium and the resulting mixture was stirred for 8 hours. After completion of the reaction was added to the mixture dropwise 5.0 g (50 mmol) of 35%hydrochloric acid, add an additional 30 ml of water, collected by filtration of the precipitated crystals, twice washed with 5 ml of water and dried in a hot-air dryer, obtaining 3.0 g (yield 88,2%) target compound as pale yellow crystals.1H-NMR-spectrum is the same as in example 6.

Example 9: Synthesis of 3-[(5-hydroxy-1-phenyl-3-Tr is formatiert-4-yl)methylthio-4,5-dihydro-5,5-dimethylisoxazole

5-Hydroxy-1-phenyl-3-cryptomaterial (2.3 g, 10 mmol)synthesized in reference example 2, and 0.6 g (15 mmol) of sodium hydroxide dissolved in 10 ml of water. Stirring the resulting solution at room temperature, was added thereto dropwise 1.7 g (20 mmol) of 35%formalin solution, and then stirred for 1 hour at the same temperature, the reaction solution 1). Separately add 2.1 g (10 mmol) of the hydrochloride [5,5-dimethyl(4,5-dihydroisoxazole-3-yl)]thiocarboxamide to 10 ml of an aqueous solution containing 1.2 g (30 mmol) of sodium hydroxide, and stirred for 1 hour, the reaction solution 2). The reaction solution 2 are added dropwise to the reaction solution 1 and the resulting mixture was stirred for 2 hours. After completion of the reaction was added to the mixture dropwise 6.0 g (60 mmol) of 35%hydrochloric acid and toluene layer obtained in the result of the operation of extraction of the two portions of 20 ml of toluene, washed with 10 ml of water, then 10 ml of saturated salt solution and dried over anhydrous sodium sulfate. After removing the toluene by distillation under reduced pressure, obtaining of 3.3 g (yield of 89.2%) of target compound in the form of a viscous material. This viscous material is left for two days, resulting in it crystallizes.

1H-NMR (300 MHz, MeOH-d4): σ=of 7.3 to 7.7 (m, 4H), 4,90 (ush., 1H), 4.16 the (s, 2H), 2,92 (s, 2H), 1,37 (C, 6N) ppm, TPL 89-92°C.

<> Example 10: Synthesis of 4-[(5-hydroxy-1-phenyl-3-cryptomaterial-4-yl)methylsulphonyl]benzene

5-Hydroxy-1-phenyl-3-cryptomaterial (2.3 g, 10 mmol)synthesized in reference example 2, and 0.6 g (15 mmol) of sodium hydroxide dissolved in 10 ml of water. Stirring the resulting solution at room temperature, was added thereto dropwise thereto 1.7 g (20 mmol) of 35%formalin solution, and then stirred for 1 hour at the same temperature. Then add to a solution of 1.6 g (10 mmol) of benzosulfimide sodium at room temperature and the resulting solution was stirred for 2 hours. After completion of the reaction was added to the mixture dropwise 6.0 g (60 mmol) of 35%hydrochloric acid and toluene layer obtained in the result of the operation of extraction of the two portions of 20 ml of toluene, washed with 10 ml of water, then 10 ml of saturated salt solution and dried over anhydrous sodium sulfate. After removing the toluene by distillation under reduced pressure, obtaining 3.4 g (yield 88.1 percent) of target compound in the form of a viscous material. This viscous material is left for two days, resulting in it crystallizes.

1H-NMR (300 MHz, MeOH-d4): σ=of 7.3 to 7.9 (m, 10H), 4,901 (ush., 1H), of 4.44 (s, 2H), 3,63 (s, 2H), 2,44 (s, 3H) ppm, TPL 122-123°C

Example 11: Synthesis of 3-[(5-hydroxy-3-cryptomaterial-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole

Hydrochloride 5-hydroxy-cryptomaterial (1.9 grams, 10 mmol)synthesized in reference example 3, and 1.2 g (15 mmol) of sodium hydroxide dissolved in 10 ml of water. Stirring the resulting solution at room temperature, was added thereto dropwise 1.7 g (20 mmol) of 35%formalin solution, and then stirred for 1 hour at the same temperature, the reaction solution 1). Separately add 2.1 g (10 mmol) of the hydrochloride [5,5-dimethyl(4,5-dihydroisoxazole-3-yl)]thiocarboxamide to 10 ml of an aqueous solution containing 1.2 g (30 mmol) of sodium hydroxide and stirred for 1 hour, the reaction solution 2). The reaction solution 2 are added dropwise to the reaction solution 1 and the resulting mixture was stirred for 2 hours. After completion of the reaction was added to the mixture dropwise 6.0 g (60 mmol) of 35%hydrochloric acid and then carefully add the sodium bicarbonate, ensuring that the reaction solution had a pH of 7. Toluene layer obtained in the result of the operation of extraction of the two portions of 20 ml of ethyl acetate, washed with 10 ml of water, then 10 ml of saturated salt solution and dried over anhydrous sodium sulfate. After removing the ethyl acetate by distillation under reduced pressure, obtaining 2.4 g (yield 81,3%) of target compound in the form of a viscous material. This viscous material is left for two days, resulting in it crystallizes.

1H-NMR (300 MHz, MeOH-d4): σ=5,35 (1H), a 4.86 (ush., 1H), 4,10 (s, 2H), 2,92 (s, 2H), 1.39 in (C, 6N) ppm

LC-MS (EI): m/z=320 (M+), 163 (base), TPL 131-133°C.

Example 12: Synthesis of 3-[(5-hydroxy-3-cryptomaterial-4-yl)methylsulphonyl]toluene

Hydrochloride 5-hydroxy-3-cryptomaterial (1.9 g, 10 mmol)synthesized in reference example 3, and 1.2 g (15 mmol) of sodium hydroxide dissolved in 10 ml of water. Stirring the resulting solution at room temperature, was added thereto dropwise 1.7 g (20 mmol) of 35%formalin solution, and then stirred for 1 hour at the same temperature. Next, add at room temperature, 1.8 g (10 mmol) of p-toluensulfonate sodium and the resulting mixture was stirred for 2 hours. After completion of the reaction was added to the mixture dropwise 5.0 g (50 mmol) of 35%hydrochloric acid, add an additional 30 ml of water, collected by filtration of the precipitated crystals, twice washed with 10 ml of water and dried in a hot-air dryer, receiving 2.67 g (yield 83,2%) target compound as pale yellow crystals.

1H-NMR (300 MHz, MeOH-d4): σ=a 7.62 (d, J=8.1 Hz, 2H), 7,37 (d, J=8.1 Hz, 2H), of 5.34 (s, 1H), 4,88 (s, 1H), 4,34 (s, 2H), 2,43 (s, 3H) ppm

LC-MS (EI): m/z=295 (M+), 163 (base), TPL 130-133°C.

Example 13: Synthesis of 4-[(3-cyano-5-hydroxy-1-phenylpyrazol-4-yl)methylsulphonyl]toluene

3-cyano-5-hydroxy-1-phenylpyrazol (1.8 g, 10 mmol)synthesized in reference example 5, and 0.6 g (15 mmol who) sodium hydroxide, dissolved in 10 ml of water. Stirring the resulting solution at room temperature, was added thereto dropwise 1.7 g (20 mmol) of 35%formalin solution, and then stirred for 1 hour at the same temperature. Then add to a solution of 1.8 g (10 mmol) of p-toluensulfonate sodium at room temperature and the resulting solution was stirred for 2 hours. After completion of the reaction was added to the mixture dropwise 5.0 g (50 mmol) of 35%hydrochloric acid, add an additional 20 ml of water, collected by filtration of the precipitated crystals, twice washed with 20 ml of water and dried in a hot-air dryer, obtaining 3.0 g (yield of 85.7%) of target compound as pale yellow crystals.

1H-NMR (300 MHz, MeOH-d4): σ=of 7.4 to 7.7 (m, N), a 4.86 (s, 1H), and 4.40 (s, 2H), 2,46 (s, 3H) ppm

LC-MS (EI): m/z=353 (M+), 197 (base), TPL 214°C.

Example 14: Synthesis of 4-[(3-carboxy-5-hydroxy-1-phenylpyrazol-4-yl)methylsulphonyl]toluene

5-Hydroxy-1-methyl-3-ethoxycarbonylphenyl (1.7 g, 10 mmol)synthesized in reference example 4, and 1.2 g (30 mmol) of sodium hydroxide dissolved in 20 ml of water. Stirring the resulting solution at room temperature, was added thereto dropwise 1.7 g (20 mmol) of 35%formalin solution, and then stirred for 1 hour at the same temperature. Then add to a solution of 1.8 g (10 mmol) of p-toluensulfonate of sodium at room temperature the resulting solution was stirred for 2 hours. After completion of the reaction was added to the mixture dropwise 5.0 g (50 mmol) of 35%hydrochloric acid, add an additional 30 ml of water, collected by filtration of the precipitated crystals, twice washed with 20 ml of water and dried in a hot-air dryer, obtaining 2.6 g (yield of 82.9%) of target compound as white crystals.

1H-NMR (300 MHz, MeOH-d4): σ=7,52 (d, J=8.1 Hz, 2H), 7,33 (d, J=8.1 Hz, 2H), around 4.85 (s, 2H), br4.61 (s, 2H), the 3.65 (s, 3H), 2,42 (s, 3H) ppm

LC-MS (EI): m/z=310 (M+), 155 (base), TPL 228°C.

Example 15: Synthesis of 4-[(3-(2,4-dichlorophenyl)-5-hydroxy-1-methylpyrazole-4-yl)methylsulphonyl]toluene

3-(2,4-Dichlorophenyl)-5-hydroxy-1-methylpyrazole (1.3 g, 5 mmol)synthesized in reference example 6, and 0.3 g (7.5 mmol) of sodium hydroxide dissolved in 5 ml of ethanol. Stirring the resulting solution at room temperature, was added thereto dropwise 1.0 g (11 mmol) of a 35%aqueous formalin solution, and then stirred for 1 hour at the same temperature. Then add to a solution of 0.9 g (5 mmol) of p-toluensulfonate sodium at room temperature and the resulting solution was stirred for 2 hours. After completion of the reaction was added to the mixture dropwise 2.5 g (25 mmol) of 35%hydrochloric acid, add an additional 15 ml of water, collected by filtration of the precipitated crystals, twice washed with 10 ml of water and dried in a hot-air dryer, obtaining 2.1 g (in the course of 90.3%) of target compound as pale yellow crystals.

1H-NMR (300 MHz, CDCl3): σ=7,0-7,4 (m, 7H), 4,24 (s, 2H), 3,69 (s, 3H), 3,50 (ush., 1H), 2,43 (s, 3H) ppm

LC-MS (EI): m/z=410 (M+), 255 (base), TPL 209°C.

Example 16: Synthesis of 4-{[(3-(3,5-dinitrophenyl)-5-hydroxy-1-methylpyrazole-4-yl]methylsulphonyl}toluene

3-(3,5-Dinitrophenyl)-5-hydroxy-1-methylpyrazole (0.65 g, 2.5 mmol)synthesized in reference example 4, and 0.15 g (3.8 mmol) of sodium hydroxide dissolved in 5 ml of ethanol. Stirring the resulting solution at room temperature, was added thereto dropwise 0.5 g (5.5 mmol) of 35%formalin solution, and then stirred for 1 hour at the same temperature. Then add to a solution of 0.45 g (2.5 mmol) of p-toluensulfonate sodium at room temperature and the resulting solution was stirred for 2 hours. After completion of the reaction was added to the mixture dropwise 2.5 g (25 mmol) of 35%hydrochloric acid, add an additional 15 ml of water, collected by filtration of the precipitated crystals, twice washed with 10 ml of water and dried in a hot-air dryer, obtaining 0.9 g (yield of 98.3%) of target compound in the form of brown crystals.

1H-NMR (300 MHz, CDCl3): σ=8,8 (t, J=2.1 Hz, 1H), charged 8.52 (d, J=1.8 Hz, 2H), 7,55 (d, J=8.1 Hz, 2H), 7,16 (d, J=8.1 Hz, 2H), 4,43 (s, 2H), 3,85 (ush., 1H), 3,76 (s, 3H), 2,31 (s, 3H) ppm

LC-MS (EI): m/z=432 (M+), 276 (base), TPL 192-194°C.

Applicability in industry.

A new industrial methods for the receipt of the 5-hydroxy-4-dimethylpyrazole connection. According to the method of the present invention 5-hydroxy-4-dimethylpyrazole compound is obtained from 5-hydroxypyrazoles compounds represented by formula (1), with high yield in a single stage using a simple and easy method under mild conditions without the use of special reaction apparatus or expensive catalyst or transition metal. In addition, practically no formation of harmful waste products from the catalyst or the transition metal, and thanks to this method is environmentally safe and is characterized by high industrial applicability.

Along with this, according to the embodiment using the method of the present invention as a solvent water offers a more environmentally friendly way, characterized by a higher degree of industrial applicability.

1. The way to obtain 5-hydroxy-4-dimethylpyrazole connection, comprising the reaction of pyrazole represented by the formula (I):

where R1denotes a hydrogen atom, a C1-C6alkyl group or phenyl group, and R2denotes an electron-withdrawing group selected from C1-C6halogenoalkanes group, halogen atom, carboxyl group and (C1-C6alkoxy)carbonyl group, or their salts with saloon the m or alkaline earth metal, ceanography, dichloraniline group and dinitroaniline group with formaldehyde and sulfur compound represented by the formula (2):

where X denotes a hydrogen atom or an alkali metal or alkaline earth metal,
R3denotes alkyl group, phenyl group, optionally substituted
With1-C6the alkyl and n is 0 or 2, or if n=0 with precursor compounds of the formula (2), in which X means carboxamidine and R3additional means 5,5-dimethyl(4,5-dihydroisoxazole-3-yl),
in the presence of a base, resulting in a gain of 5-hydroxy-4-dimethylpyrazole compound represented by the formula (3):

where R1, R2, R3and n have the same meanings as above.

2. The method according to claim 1, in which n is 0.

3. The method according to claim 1, in which n is 2.

4. The method according to any one of claims 1 to 3, in which the electron-withdrawing group represented by the symbol R2is triptorelin group.

5. The method according to any one of claims 1 to 3, in which the electron-withdrawing group represented by the symbol R2is cyano.

6. The method according to any one of claims 1 to 3, in which the electron-withdrawing group represented by the symbol R2is alkoxycarbonyl group, carboxyl group or its salt with Melo the major or alkaline earth metal.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R is hydrogen or (lower)alkyl; R1 is a (lower)alkyl or (C3-C7)cycloalkyl; X is nitrogen while Y is carbon or Y is nitrogen while X is carbon; m equals 0 or 1; Z is C(O) or SO2; R2 is selected from a group consisting of (lower)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl substituted with (lower)alkyl, (lower)phenylalkyl, where the phenyl ring is not substituted or is mono- or disubstituted with (lower)alkoxy or halide, pyridyl which is mono- or disubstituted with a halide, and NR3R4 or when Z is C(O), R2 can also be a (lower)alkoxy; R3 is hydrogen or (lower)alkyl; R4 is selected from a group consisting of (lower)alkyl, (lower)alkoxyalkyl, (C3-C7)cycloalkyl, unsubstituted phenyl or phenyl which is mono-substituted with (lower)alkoxy, or (lower)phenylalkyl, where phenyl is not substituted or is mono- or disubstituted with a halide; or R3 and R4 together with the nitrogen atom to which they are bonded form a 5-, 6- or 7-member heterocyclic ring which optionally contains an additional heteroatom selected from oxygen, the said heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from (lower)alkyl, halide and alkyl halide, or is condensed with a phenyl or cyclohexyl ring, and to their pharmaceutically acceptable salts, as well as to pharmaceutical compositions containing these compounds.

EFFECT: obtaining novel compounds and pharmaceutical compositions based on the said compounds, which are suitable for treating and/or preventing diseases which are associated with modulation of H3 receptors.

25 cl, 2 tbl, 93 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cycloalkene derivatives of formula (I) in which X and Y are a group, in which X and Y together with a carbon atom on ring B to which they are bonded form a ring A, X and Y together represent a ring B substitute, or each of X and Y is a hydrogen atom.

EFFECT: invention relates to a medicinal agent based on the said compounds, which has inhibitory effect on intracellular signal transduction or cell activation induced by an endotoxin.

21 cl, 3 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound or its salt of formula 1: , where A, E, D, R0, R1-R4 and a assume values given in the formula of invention. The invention also relates to an antioxidant medicinal agent.

EFFECT: effectiveness during treatment of ischemic diseases of organs, during treatment of diseases caused by oxidation cell disorders and when inhibiting disorders of the retina.

4 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: novel compound is N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or its pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with CFTR activity modulation properties.

2 cl, 485 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-phenylpyrimidine-2-carbonitrile of formula

(values of R, R1, R2 are given in the formula of invention) or their pharmaceutically acceptable salts which have inhibition properties towards catepsin K and catepsin S. The invention also relates to use of derivatives of formula I for treating catepsin K and catepsin S related disorders, as well as to a pharmaceutical composition containing the said derivative.

EFFECT: improved properties of derivatives.

9 cl, 151 ex

FIELD: chemistry.

SUBSTANCE: invention proposes 5-member heterocyclic inhibitors of kinase p38, including kinase p38α and kinase p38β, based on pyrazoles and imidazoles, with the general formula given below , in which ring B is phenyl, and C is a pyrazole or imidazole ring, and the rest of the symbols assume values given in paragraph 1 of the formula of invention.

EFFECT: there are described pharmaceutical compositions containing said compounds, as well as methods of using the compounds and compositions, including a method of treating, preventing or suppressing one or more symptoms of diseases and conditions mediated by kinase p38 which include, but not limited to, inflammatory diseases and conditions.

31 cl, 6 tbl, 175 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula compounds, as well as their pharmaceutically acceptable salts, a pharmaceutical composition based on them, with inhibitory activity towards phosphorylation of protein Tau, and to methods of producing said compounds. In formula (I), R5 is aryl, aryl(C1-C6)alkyl; R6 is halogen; R3 is (C1-C6)alkyl, possibly substituted with substitutes selected from halogen, OH, NH2, azetidine; or monocyclic aryl or heteroaryl, such as thiophene or pyridine, possibly substituted with substitutes selected from NO2, CN, (C1-C6)alkoxy, (C1-C6)alkyl; or CONR1R2, SO2Ra, C(=NH)R1b, COOR1c; R1, R2 independently represent a hydrogen atom, possibly substituted with one halogen atom, (C1-C6)alkyl, moncyclic aryl or monocyclic 5- or 6-member heteroaryl containing 1 or 2 heteroatoms, such as S, O, N, possibly substituted with one or more substitutes selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, trifluoromethyl, N(CH3)2; or R1 and R2 can form a 5- or 6-member ring which optionally contains a heteroatom such as N; R1a is aryl, possibly substituted with (C1-C6)alkoxy; R1b is (C1-C6)alkyl, possibly substituted aryl or 6-member heteroaryl, containing 1 or 2 N atoms, where the substitute is (C1-C6)alkoxyl; R1c is (C1-C6)alkyl, (C2-C6)alkenyl; and their pharmaceutically acceptable salts.

EFFECT: aminoindazole derivatives as kinase inhibitor.

8 cl, 44 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for synthesis of 1-phenyl-2,3-dimethyl-4-iodopyrazolone-5 (iodoantipyrine) representing a medicinal preparation. Invention proposes a method for synthesis of iodoantipyrine by electrophilic iodination of antipyrine or antipyrine benzene sulfoacid under conditions of mechanical activation without solvent being both at the synthesis step and the isolation step. Using the proposed method provides preparing pharmacopoeia iodoantipyrine with the yield 57-96% depending on the parent substrate and an iodinating reagent, significant simplifying the process for its synthesis and the complete excluding an organic solvent.

EFFECT: improved method of synthesis.

4 ex

FIELD: organic chemistry, medicinal virology, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazole of the formula (I-A):

wherein R1 means (C1-C12)-alkyl that can be optionally substituted with 1-3 substitutes taken among fluorine, chlorine and bromine atoms, (C3-C8)-cycloalkyl, phenyl, pyridyl or (C1-C4)-alkyl substituted with phenyl; R2' means optionally substituted phenyl wherein phenyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano- and nitro-group; R3 means (C1-C12)-alkyl or (C1-C4)-alkoxy-(C1-C4)-alkyl; A' means (C1-C4)-alkyl optionally substituted with phenyl or optionally substituted with 4-pyridyl wherein phenyl or 4-pyridyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH2-U-heterocyclyl wherein U represents O, S or NR'' wherein R'' means hydrogen atom or (C1-C4)-alkyl and wherein heterocyclyl means pyridyl or pyrimidinyl that is optionally substituted with 1-2 substitutes taken among (C1-C4)-alkyl, fluorine, chlorine and bromine atoms, cyano-, nitro-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH(OH)-phenyl; or A' means the group CH=CHW wherein W means phenyl; X means S or O, and their pharmaceutically acceptable salts. These compounds are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and, therefore, can be used in treatment of HIV-mediated diseases. Also, invention relates to a pharmaceutical composition used in treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

The invention relates to the field of synthesis of biologically active compounds, and to methods of producing N-ACI-derivatives of 4-aminoantipyrine, analgesic and anti-inflammatory action

The invention relates to 4-(allumination)-2,4-dihydropyrazol-3-Onam General formula I, where R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, unsubstituted or substituted once to three - fold amino, acyl, halogen, nitro, CN, AO, carboxyla, carbamoyl, N-allylcarbamate, N, N-dialkylammonium (with 1-6 C-atoms in the alkyl part), A-CO-NH-, AND-O-CO-NH-, AND-O-CO -, NA-, SO2NR4R5(R4and R5can denote H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, or O, which may be substituted),-CO-NH-SO2-, A-CO-NA-SO2- (AND-SO2-)2N-, tetrazolium phenyl; or pyridyl; R2denotes alkyl with 1-5 C-atoms, ethoxycarbonylmethyl, hydroxycarbonylmethyl; R3denotes unbranched or branched alkyl with 1-5 C-atoms, unbranched or branched alkoxy with 1-5 C-atoms or CF3And denotes unbranched or branched alkyl with 1-6 C-atoms or CF3and their salts

The invention relates to the field of organic chemistry, in particular to a method for producing 1-phenyl-2,3-dimethyl-4-iteration-5 (yodanthipirina), which is the drug

The invention relates to 2-[(dihydro)pyrazolyl-3'-oxymethylene] anilides formula I

< / BR>
in whichmeans simple or double bond, and the index and the substituents have the following meanings:

n means 0, 1 or 2;

m means 0, 1 or 2 and the substituents R2may be different if m is greater than 1;

X represents a direct bond, O or NRa;

Rameans hydrogen;

R1means halogen or C1-C4alkyl, or, if n is 2, represents optionally associated with two adjacent ring atoms of the hydrocarbon bridge containing 3 or 4 carbon atoms;

R2means nitro, halogen, C1-C4alkyl, C1-C4halogenated or1-C4alkoxycarbonyl;

R3means optionally substituted alkyl, optionally substituted saturated cycle or optionally substituted single or dual core aromatic radical, which together with the carbon atoms may contain as members of the cycle from one to four nitrogen atoms;

R4means hydrogen, optionally substituted alkyl;

The invention relates to a method for producing 1-phenyl-2,3-dimethyl-4 iteration-5 (yodanthipirina) with antipyretic antineuralgic action, part antiemeticski drugs such as Felsol, Vastylu and also shown high activity against tick-borne encephalitis

The invention relates to the derivatives of pyrazole, specifically to N-phenylpyrazole, which can find application in agriculture

The invention relates to the derivatives of arylpyrazole, and to their use in compositions for the destruction of arthropod, nematode, helminth and protozoan pests

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of common formula (I) , in which: A, if available, means (C1-C6)-alkyl; R1 means group NR6R7, (C4-C7)-azacycloalkyl, (C5-C9)-azabicycloalkyl, besides, these groups, unnecessarily, are substituted with one or more substituents, selected from (C1-C5)-alkyl or halogen; A-R1 is such that nitrogen of radical R1 and nitrogen in position 1 of pyrazole are necessarily separated at least by two atoms of carbon; R3 means radical H, OH, NH2, ORc, NHC(O)Ra or NHSO2Ra; R4 means phenyl or heteroaryl, unnecessarily, substituted with one or more substituents, selected from halogen, CN, NH2, OH, ORc, C(O)NH2, phenyl, polyfluoroalkyl, linear or ramified (C1-C6)-alkyl, besides these substituents, unnecessarily, are substituted with halogen, and moreover, heteroaryl radicals are 3-10-member, containing one or more heteroatoms, selected from sulphur or nitrogen; R5 means radical H, linear or ramified (C1-C6)-alkyl; Ra means linear or ramified (C1-C6)-alkyl; Rc means linear or ramified (C1-C6)-alkyl, (poly)fluoroalkyl or phenyl; R6 and R7, independently from each other, means hydrogen, (C1-C6)-alkyl; R6 and R7 may create 5-, 6- or 7-member saturated or non-saturated cycle, which includes one heteroatom, such as N, and which, unnecessarily, substituted with one or more atoms of halogen; to its racemates, enantiomers, diastereoisomers and their mixtures, to their tautomers and their pharmaceutically acceptable salts, excluding 3-(3-pyridinyl)-1H-pyrazole-1- butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine. Invention is also related to methods for production of compounds of formula (I) and to pharmaceutical composition intended for treatment of diseases that appear as a result of disfunction of nicotine receptors α7 or favorably responding to their modulation, on the basis of these compounds.

EFFECT: production of new compounds and pharmaceutically acceptable composition on their basis, which may find application in medicine for treatment, prophylaxis, diagnostics and observance over development of psychiatric or neurological disorders or diseases of central nervous system, when cognitive functions deteriorate or quality of sensor information processing drops.

16 cl, 106 ex

Up!