Method for preparing substituted aniline compound (variants) and intermediate compounds

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a novel method that can be used in industry for synthesis of substituted aniline compound represented by the following general formula (6):

wherein in the general formula (6) each R1, R2 and R3 means independently alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group, alkylcarboxamide group, nitro-group, aryl group, arylalkyl group, aryloxy-group, halogen atom or hydrogen atom; each X and Y means independently hydrogen atom, alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group or halogen atom. Method involves oxidation of substituted indole compound represented by the following general formula (3):

(wherein values R1, R2, R, X and Y are given above) resulting to opening indole ring to yield acetanilide compound represented by the following general formula (4):

(wherein values R1, R2, R3, X and Y are given above) and Ac means acetyl group, and treatment of this compound by reduction and deacetylation. Also, invention relates to novel intermediate compounds. Proposed compound (6) can be used as intermediate substance for production of chemicals for agriculture and as medicinal agents.

EFFECT: improved method of synthesis.

20 cl, 1 sch, 3 tbl, 31 ex

 

The present invention relates to a method for substituted aniline compounds, which can be used as intermediate compounds in the production of, for example, chemicals for agriculture and pharmaceuticals.

It is now known that some of sulfonanilide derivatives containing 4,6-dimethoxypyrimidine have high herbicide activity (see Japanese patent JP-A-11-60562 and international publication WO00/06553). In addition, it is also known that upon receipt of these derivatives substituted aniline compound used as the primary intermediate compounds.

To date, describes how to obtain the substituted aniline compounds, which is the main intermediate connection for sulfonanilide derived with high herbicide activity (see Japanese patent JP-A-7-48359, international publication WO96/41799). Each specified method is carried out by reaction, which is disadvantageous for production; it is therefore desirable to develop a method by which you can profitably be produced in industry specified substituted aniline.

To solve the above problems, the applicant of the present invention conducted the study. The study found that FR is specified substituted aniline compound can be obtained by interaction, for example, (pyrimidine-2-yl)-2-propranololo connection with hydrazine powered compound in the presence of the acid with the formation of substituted indole compounds, oxidation of substituted indole compounds, leading to the disclosure of the indole ring with getting acetanilide connection, and restore acetanilide connection preferably with sodium borohydride or deacetylation amide fragment, that is, the data obtained indicate that the above problem can be solved. The obtained data allowed to complete the present invention.

The present invention is described in detail below.

The above problem is solved, mainly in the inclusion of the following inventions [1] [14].

[1] the Method of obtaining substituted aniline compounds represented by the following General formula (6):

(where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitro-group, aryl group, arylalkyl group, alloctype, halogen atom or hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxy who lilou group, halogenating group, carboxyl group, alkoxycarbonyl group or halogen atom), characterized in that the method comprises the oxidation of substituted indole compounds represented by the following General formula (3):

(where R1, R2, R3X and Y have the same definitions as given above), leading to the disclosure of the indole ring with getting acetanilide compounds represented by the following General formula (4):

(where R1, R2, R3X and Y have the same definitions as given above; and AC is an acetyl group), and the processing of this connection through recovery and deacetylation.

[2] the Method of obtaining substituted aniline compounds represented by the following General formula (6):

(where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitro-group, aryl group, arylalkyl group, alloctype, halogen atom or hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation the group, carboxyl group, alkoxycarbonyl group or halogen atom), characterized in that the method comprises the oxidation of substituted indole compounds represented by the following General formula (3):

(where R1, R2, R3X and Y have the same definitions as given above), leading to the disclosure of the indole ring with getting acetanilide compounds represented by the following General formula (4):

(where R1, R2, R3X and Y have the same definitions as given above; and AC is an acetyl group), restoring the connection with obtaining 2-(pyrimidine-2-elgeroctober)acetanilide compounds represented by the following General formula (5):

(where R1, R2, R3X, Y and Ac have the same definitions as given above), and successively carrying out the deacetylation.

[3] the Method of obtaining substituted aniline compounds represented by the following General formula (6):

(where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, nitrogroup is, aryl group, arylalkyl group, alloctype, halogen atom or hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or halogen atom), characterized in that the method comprises the oxidation of substituted indole compounds represented by the following General formula (3):

(where R1, R2, R3X and Y have the same definitions as given above), leading to the disclosure of the indole ring with getting acetanilide compounds represented by the following General formula (4):

(where R1, R2, R3X and Y have the same definitions as given above; and AC is an acetyl group), restore the connection without the allocation of obtaining 2-(pyrimidine-2-elgeroctober)acetanilide compounds represented by the following General formula (5):

(where R1, R2, R3X, Y and AC have the same definitions as given above), and successively carrying out the deacetylation.

[4] the Method of obtaining substituted aniline compounds represented by the following General formula (6):

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(where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitro-group, aryl group, arylalkyl group, alloctype, halogen atom or hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or halogen atom), characterized in that the method comprises the oxidation of substituted indole compounds represented by the following General formula (3):

(where R1, R2, R3X and Y have the same definitions as given above), leading to the disclosure of the indole ring with getting acetanilide compounds represented by the following General formula (4):

(where R1, R2, R3X and Y have the same definitions as given above; and AC is an acetyl group), deacetylation this connection with obtaining the amino compounds represented by the following General formula (7):

(where R1, R2, R3X and Y have the same definitions as given above), and then about the introduction of recovery.

[5] a method of obtaining a substituted aniline compound according to any of the above methods 1-4, where the substituted indole compound represented by the following General formula (3):

(where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitro-group, aryl group, arylalkyl group, alloctype, halogen atom or hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or halogen atom), produced by the interaction, in the presence of acid, 2-(pyrimidine-2-yl)-2-propranololo compounds represented by the following General formula (1):

(where R1, R2and R3have the same definitions as given above), with hydrazine powered by the connection represented by the following General formula (2):

(where X and Y have the same definitions as given above).

[6] the Method of obtaining the amino compounds represented by the following General formula (7):

(where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitro-group, aryl group, arylalkyl group, alloctype, halogen atom or hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or halogen atom), characterized in that the method comprises the oxidation of substituted indole compounds represented by the following General formula (3):

(where R1, R2, R3X and Y have the same definitions as given above), leading to the disclosure of the indole ring with getting acetanilide compounds represented by the following General formula (4):

(where R1, R2, R3X and Y have the same definitions as given above; and AC is an acetyl group), and deacetylation this connection.

[7] the Method of obtaining 2-(pyrimidine-2-elgeroctober)acetanilide compounds represented by the following General formula (5):

(where R1, R2and R each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitro-group, aryl group, arylalkyl group, alloctype, halogen atom or hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or a halogen atom; and AC is an acetyl group), characterized in that the method comprises the oxidation of substituted indole compounds represented by the following General formula (3):

(where R1, R2, R3X and Y have the same definitions as given above), leading to the disclosure of the indole ring with getting acetanilide compounds represented by the following General formula (4):

(where R1, R2, R3X and Y have the same definitions as given above; and AC is an acetyl group), and restore the connection.

[8] the Method of obtaining 2-(pyrimidine-2-elgeroctober)acetanilide compounds represented by the following General formula formula (5):

(where R1, R2and R each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitro-group, aryl group, arylalkyl group, alloctype, halogen atom or hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or a halogen atom; and AC is an acetyl group), characterized in that the method comprises the oxidation of substituted indole compounds represented by the following General formula (3):

(where R1, R2, R3X and Y have the same definitions as given above), leading to the disclosure of the indole ring with getting acetanilide compounds represented by the following General formula (4):

(where R1, R2, R3X, Y and AC have the same definitions as given above), and restore the connection without his or her selection.

[9] the Method of obtaining substituted indole compounds represented by the following General formula (3):

(where R1, R2and R3each independently mean alkyl g is the SCP, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitro-group, aryl group, arylalkyl group, alloctype, halogen atom or hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or halogen atom), characterized in that the method comprises the interaction, in the presence of acid (pyrimidine-2-yl)-2-propranololo compounds represented by the following General formula (1):

(where R1, R2and R3have the same definitions as given above), with hydrazine powered by the connection represented by the following General formula (2):

(where X and Y have the same definitions as given above).

[10] the Method of obtaining acetanilide compounds represented by the following General formula (4):

(where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitro-group, aryl group, arylalkyl the group, alloctype, halogen atom or hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or a halogen atom; and AC is an acetyl group), characterized in that the method comprises the oxidation of substituted indole compounds represented by the following General formula (3):

(where R1, R2, R3X and Y have the same definitions as given above), leading to the disclosure of the indole ring.

[11] the Method of obtaining the amino compounds represented by the following General formula (7):

(where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitro-group, aryl group, arylalkyl group, alloctype, halogen atom or hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or halogen atom), characterized in that the method comprises the deacetylation acetanilide the th connections, represented by the following General formula (4):

(where R1, R2, R3X and Y have the same definitions as given above; and AC is an acetyl group).

[12] the Method of obtaining substituted aniline compounds represented by the following General formula (6):

(where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitro-group, aryl group, arylalkyl group, alloctype, halogen atom or hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or halogen atom), characterized in that the method comprises the recovery of the amino compounds represented by the following General formula (7):

(where R1, R2, R3X and Y have the same definitions as given above).

[13] the Method of obtaining 2-(pyrimidine-2-elgeroctober)acetanilide compounds represented by the following General formula (5):

(where R1, R and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitro-group, aryl group, arylalkyl group, alloctype, halogen atom or hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or a halogen atom; and AC is an acetyl group), characterized in that the method comprises restoring acetanilide compounds represented by the following General formula (4):

(where R1, R2, R3X, Y and AC have the same definitions as given above).

[14] the Method of obtaining substituted aniline compounds represented by the following General formula (6):

(where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitro-group, aryl group, arylalkyl group, alloctype, halogen atom or hydrogen atom; and X and Y each independently denotes an atom is odorata, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or halogen atom), characterized in that the method comprises the deacetylation of 2-(pyrimidine-2-elgeroctober)acetanilide compounds represented by the following General formula (5):

(where R1, R2, R3X and Y have the same definitions as given above; and AC is an acetyl group).

The present invention is described in detail below.

In the method according to the present invention, described in paragraph [1] (in this text the term "method according to the present invention has the same value if not specified), use of substituted indole compound represented by the General formula (3)as a raw material. Specified substituted indole compound represented by the General formula (3)can be obtained by the interaction (pyrimidine-2-yl)-2-propranololo compounds represented by the General formula (1)with hydrazine powered by the connection represented by the General formula (2), in the presence of acid. Therefore, first describe stage (stage 1) obtain the substituted indole compounds represented by the General formula (3).

First of all described (pyrimidine-2-yl)-2-propanone connection, provided the General formula (1), and hydrazine powered compound represented by the General formula (2), which are used as raw materials.

In (pyrimidine-2-yl)-2-propranolol the compound represented by General formula (1), R1, R2and R3each can independently contain from 1 to 6 carbon atoms (in this text, the carbon atoms when their number is, for example, from 1 to 6 carbon atoms, represented by the abbreviation "C1-C6") and represent (C1-C6)alkyl group with straight or branched chain, such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, sec-bucilina group, tert-bucilina group, n-pencilina group, n-exilda group or the like; (C1-C6)alkoxygroup straight or branched chain, such as methoxy group, ethoxypropan, n-propoxylate, isopropoxide or the like; (C1-C6)alkoxy(C1-C6)alkyl group with straight or branched chain, such as methoxymethyl group, ethoxyethylene group, amoxicilina group or the like; (C1-C6)halogenating group with a straight or branched chain, such as permetrina group, deformational group, triptorelin group or the like; carboxyl group; (C1-C6)alkoxycarbonyl group with a straight or branched chain, such as methoxycarbonyl GRU is PA, ethoxycarbonyl group or the like; (C1-C6)alkylcarboxylic group with a straight or branched chain, such as methylcobalamine group, ethylcarbodiimide group or the like; a nitro-group; aryl group such as phenyl group or the like; aryl(C1-C6)alkyl group with straight or branched chain, such as phenylmethylene group, phenylethylene group or the like; alloctype, such as fenoxaprop, naftussya or the like; halogen atom such as bromine atom, chlorine atom, fluorine atom, iodine atom or the like; or the hydrogen atom.

Therefore, as (pyrimidine-2-yl)-2-propranololo compounds represented by the General formula (1)used in stage 1, mention should be made of, for example, 1-(pyrimidine-2-yl)-2-propanone, 1-(4,6-dimethylpyrimidin-2-yl)-2-propanone, 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone, 1-(4,6-dimethoxy-5-methylpyrimidin-2-yl)-2-propanone, 1-(4,6-dimethoxy-5-ethylpyrimidine-2-yl)-2-propanone, 1-(4,6-dimethoxy-5-nitropyrimidin-2-yl)-2-propanone, 1-(4,6-dichloropyrimidine-2-yl)-2-propanone, 1-(4,6-dimethoxy-5-ethoxycarbonylpyrimidine-2-yl)-2-propanone and 1-(4,6-detoxification-2-yl)-2-propanone. (Pyrimidine-2-yl)-2-propanone the connection represented by the General formula (1), tautomers, and any of the tautomers can be used in the method according to the present invention. Od is ako in the present description, the connection structure is depicted in the form of 2-propranololo derivative, as can be seen in the General formula (1), and the title compound is 2-propanone derived, as shown above.

These (pyrimidine-2-yl)-2-propanone compounds represented by the General formula (1)are known compounds or compounds which can be obtained from the raw material, such as 2-phenylsulfonyl-4,6-dimethylpyrimidin or the like, according to the method described in the publication Chemical & Pharmaceutical Bulletin, p. 152 (1982). (Pyrimidine-2-yl)-2-propanone the connection represented by the General formula (1), includes new connections, for example, 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone, and this connection is the raw material used in obtaining the substituted aniline compound represented by the General formula (6).

Meanwhile, in the General formula (2) X and Y each independently can represent a (C1-C6)alkyl group with straight or branched chain, such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, sec-bucilina group, tert-bucilina group, n-pencilina group, n-exilda group or the like; (C1-C6)alkoxygroup straight or branched chain, such as methoxy group, ethoxypropan, n-propoxylate, isopropoxide or the like; (C1-C6)alkoxy(C1-C6)alkyl group with straight or branched what EPU, such as methoxymethyl group, ethoxyethylene group, amoxicilina group or the like; (C1-C6)halogenating group with a straight or branched chain, such as permetrina group, deformational group, triptorelin group or the like; carboxyl group; (C1-C6)alkoxycarbonyl group with a straight or branched chain, such as methoxycarbonyl group, ethoxycarbonyl group or the like; halogen atom such as bromine atom, chlorine atom, fluorine atom, iodine atom or the like; or a hydrogen atom.

So as hydrazine powered compound represented by the General formula (2)used in stage 1, mention should be made of, for example, phenyl, 2-methylphenylhydrazine, 4-methylphenylhydrazine, 2,4-dimethylbenzylidene, 2-ethylphenidate, 4-ethylphenidate, 4-isopropylpiperazine, 2-methoxyphenylhydrazine, 4-methoxyphenylhydrazine, 2-methoxyethylmercury, 4-methoxymethamphetamine, 4-triftormetilfullerenov, 2-hydrazinophenyl acid, 4-ethoxycarbonylpyrimidine and 2-chlorophenylhydrazone.

Hydrazine powered compound represented by the General formula (2)may be in free form or in the form of salts (e.g. as hydrochloride or sulfate).

Hydrazine powered compound represented by the General formula (2)is known to connect the discharge or connection, which can be obtained from the corresponding crude aniline according to method described in the publication Journal of Organic Chemistry, p. 2849 (1972).

In this regard, hydrazine powered compounds represented by the General formula (2), 2-methoxyethylmercury is a new connection.

In stage 1 to obtain the substituted indole compounds represented by the General formula (3), the molar ratio of hydrazine powered compound represented by the General formula (2), and (pyrimidine-2-yl)-2-propranololo compounds represented by the General formula (1)may be at any level for the implementation of the interaction between the two compounds. However, (pyrimidine-2-yl)-2-propanone the connection represented by the General formula (1), used in quantity, for example, is usually from 0.5 to 3 moles, preferably 1-2 moles per mole of hydrazine powered compound represented by the General formula (2).

In stage 1 getting substituted indole compounds represented by the General formula (3), is performed with the use of acid. As examples of the acid can be a mineral acid such as hydrochloric acid, sulfuric acid and the like; acetic acid, such as acetic acid, triperoxonane acid and the like; a Lewis acid such as zinc chloride, boron TRIFLUORIDE and the like, sulfonic acid, such as p-toluensulfonate and the like; phosphoric acids such as polyphosphoric acid and the like; halogen compounds of phosphorus, such as phosphorus trichloride, and the like; and acidic ion exchange resins such as Amberlist and the like. The use of a Lewis acid such as zinc chloride, boron TRIFLUORIDE or the like, is preferred. The amount of acid used in stage, can be any number, because it does not decompose educated substituted indole compound represented by the General formula (3); however, the number can be from 0.001 to 10 moles, preferably from 0.1 to 2 moles per mole of hydrazine powered compound represented by the General formula (2).

Stage 1 get substituted indole compounds represented by the General formula (3), can be performed sufficiently even in conditions without solvent, but can be done using the solvent. The solvent used in this reaction may be any solvent, provided that it does not affect the reaction. In this regard, we can mention, for example, aromatic hydrocarbons such as toluene, xylene, chlorobenzene and the like; halogenated aliphatic hydrocarbons, such as dichloromethane, chloroform and the like; esters of acetic acid such as mutilate is at, ethyl acetate, butyl acetate and the like; aprotic polar solvents such as dimethylformamide, dimethylacetamide, N-organic, tetramethylrhodamine, hexamethylphosphoramide (NMRA) and the like; solvents of the type of simple ether, such as diethyl ether, tetrahydrofuran, dioxane and the like; and aliphatic hydrocarbons such as pentane, n-hexane, and the like. Aromatic hydrocarbons such as toluene and the like, are preferred. These solvents can be used as a single solvent or a mixed solvent with any mixture. You can use any amount of solvent, as it allows sufficient mixing of the reaction system, but the number is usually from 0.5 to 20 liters, preferably from 1 to 10 liters per mole of hydrazine powered compound represented by the General formula (2).

The reaction temperature used in stage 1 obtain the substituted indole compounds represented by the General formula (3)is, for example, from 0°With up to temperature phlegmy used solvent, preferably from 0°to 120°C.

Special restrictions regarding the time of the reaction used in stage 1 obtain the substituted indole compounds represented by the General formula (3, does not exist, however the preferred time of reaction is from 0.5 hours to 12 hours.

Substituted indole compound represented by the General formula (3), which can be obtained at stage 1, is a new compound and is used as intermediate compounds for sulfonanilide derived, which, as you know, has a high herbicide activity and is effective.

The method according to the present invention includes a step (stage 2) oxidation of the indole ring in the above substituted indole compounds represented by the General formula (3), leading to ring opening with obtaining substituted acetanilide compounds represented by the General formula (4), and stage sequential processing acetanilide compounds represented by the General formula (4), by restoring and deacetylation to obtain the final product, i.e. substituted aniline compounds represented by the General formula (6). Any reactions recovery and deacetylation may be performed first. Therefore, the description is given in the following order, after stage 2 should stage (stage 3) interaction acetanilide compounds represented by the General formula (4), preferably sodium borohydride to obtain 2-(pyrimidine-2-alhydrogel the Il)acetamide connection represented by the General formula (5), and stage (stage 4) deacetylation amide fragment 2-(pyrimidine-2-elgeroctober)acetanilide compounds represented by the General formula (5)obtained in stage 3, you get the final product, i.e. the substituted aniline compound represented by the General formula (6).

Stage 2 is a stage of oxidation of substituted indole compounds represented by the General formula (3)obtained in stage 1, leading to the disclosure of the indole ring with obtaining substituted acetanilide compounds represented by the General formula (4). In this regard, in the General formula (3) R1, R2, R3X and Y have the same definitions as given above.

The oxidant used in stage 2, can serve as ozone; inorganic peroxides such as hydrogen peroxide and the like; organic peroxides such as peracetic acid, natantia acid, m-chlormadinone acid and the like; metallic oxides, such as potassium permanganate, periodate sodium, sodium tungstate, ammonium molybdate, and the like; and the air. Preferred is ozone. These oxidants can provide sufficient interaction even when using oxidizing agents in the form of one of an oxidant, but can be applied in any mixture. At the stage of oxidation this is the procedure oxidant can be used in any quantity, provided that the oxidizer does not destroy the formed substituted acetanilides the connection represented by the General formula (4), but usually the amount is from 0.1 to 20 moles, preferably from 1 to 10 moles per mole of substituted indole compounds represented by the General formula (3).

In stage 2 the reaction is usually carried out using a solvent. Can be used any solvent, provided that it does not affect the reaction. In this connection it should be mentioned, for example, esters of acetic acid such as methyl acetate, ethyl acetate, butyl acetate and the like; halogenated aliphatic hydrocarbons, such as dichloromethane, chloroform and the like; aromatic hydrocarbons such as toluene, xylene, chlorobenzene and the like; aliphatic hydrocarbons such as pentane, n-hexane and the like; aprotic polar solvents such as formamide, dimethylformamide, dimethylacetamide and the like; NITRILES such as acetonitrile and the like; solvents of the type of simple ether, such as diethyl ether, tetrahydrofuran, dioxane, diglyme and the like; alcohols such as methanol, ethanol and the like; carboxylic acids such as acetic acid and the like; ketones, such as acetone, methyl isobutyl ketone and the like; and water. The solvents can be used in owani in a single solvent or a mixed solvent of any of the mixture. Can be used any number of solvent, provided that it provides sufficient stirring of the reaction system, but the number is usually from 0.5 to 20 liters, preferably from 1 to 10 liters per mole of substituted indole compounds represented by the General formula (3).

The reaction temperature in stage 2 may be, for example, from -20°With up to temperature phlegmy solvent used, but the preferred temperature is from -10°C to 60°C.

Special restrictions regarding the timing of the reaction in stage 2 is not available. However, the preferred time of reaction is from 0.5 hours to 12 hours.

Substituted acetanilide compounds represented by the General formula (4)obtained in stage 2, are new compounds and are used as intermediate compounds for sulfonanilide derived, which is used, as is well known, as a herbicide.

Thus, it can be obtained substituted acetanilides the connection represented by the General formula (4).

As acetanilide compounds represented by the General formula (4), mention should be made of, for example, 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide, 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-methylacetanilide, 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-etiracetam the lead, 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethoxyethylacetate, 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-4-methylacetanilide, 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-4-ethylacetamide, 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-4-ethoxyethylacetate, 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-4-chloroacetanilide, 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-chloroacetanilide, 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-4-forcefield and 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-forcefield.

Substituted acetanilides the connection represented by the General formula (4)obtained in stage 2 can then be used in stage 3 without isolation or purification. That is, the substituted indole compound represented by the General formula (3), is subjected to oxidation and ring opening at stage 2 through, for example, ozone or the like and sequentially subjected to the recovery stage 3, described later, preferably by sodium borohydride in the same vessel; thus 2-(pyrimidine-2-elgeroctober)acetanilide the connection represented by the General formula (5)can be easily obtained and the subsequent processing of the used oxidant is also easy. Therefore, from the viewpoint of ease of the process and so on, preferably on an industrial scale to apply the method includes the stage of this OK the comprehension and the disclosure of the ring and the stage of such recovery continuously in the same vessel.

Next will be described in stage 3.

Stage 3 is a stage of recovery acetanilide compounds represented by the General formula (4), preferably by means of sodium borohydride to obtain 2-(pyrimidine-2-elgeroctober)acetanilide compounds represented by the General formula (5). In this case, in the General formula (4) R1, R2, R3X and Y have the same definitions as given above.

At stage 3 the molar ratio of substituted acetanilide compounds represented by the General formula (4), and sodium borohydride can be on any level, however, the amount of sodium borohydride may be from 0.5 to 20 moles, preferably from 1 to 10 moles per mole of substituted acetanilides connection.

The reaction in stage 3 is usually carried out using a solvent. Used in stage 3, the solvent can be any solvent, provided that it does not affect the reaction. In this connection it should be mentioned, for example, aromatic hydrocarbons such as toluene, xylene, chlorobenzene and the like; esters of acetic acid such as methyl acetate, ethyl acetate, butyl acetate and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and the like; aprotic polar solvents such as dimethylformamide, dimethylacetamide and the like; Rast is oriali type of simple ether, such as diethyl ether, tetrahydrofuran, dioxane and the like; aliphatic hydrocarbons such as pentane, n-hexane and the like; glycols such as polyethylene glycol (PEG)-400 and the like; and water. The solvents can be used as a single solvent or a mixed solvent of any of the mixture. Can be used any number of solvent, provided that it allows sufficient mixing of the reaction system, but the number is usually from 0.5 to 20 liters, preferably from 1 to 10 liters per mole of substituted acetanilide compounds represented by the General formula (4).

The reaction temperature in stage 3 may be, for example, -15°With up to temperature phlegmy solvent used, but the preferred temperature is from -5°C to 60°C.

Special restrictions regarding the timing of the reaction in stage 3 are not available, but the preferred time of reaction is from 0.5 hour to 24 hours.

In this case, at stage 3, it is preferable to use sodium borohydride because of the stability of the reagent, but also due to the fact that the reagent is used for subsequent processing used in stage 2 of the oxidizing agent, which carries out the oxidative ring opening of substituted indole SOEDINENIYa recovery stage 3 is not limited to recovery of the sodium borohydride and can be carried out, for example, by catalytic hydrogenation (catalyst can be used palladium on coal [Pd/C], platinum, coal [Pt/C], the Raney catalyst (e.g., Raney Nickel) or commonly used for catalytic reduction of metal catalyst), restoring sociallyengaged or restore the DIBORANE.

2-(Pyrimidine-2-elgeroctober)acetanilide the connection represented by the General formula (5)obtained in stage 3, can as such be used in the next stage 4 without highlighting.

The following describes the holding stage 4.

In stage 4 of 2-(pyrimidine-2-elgeroctober)acetanilide the connection represented by the General formula (5)obtained in stage 3, is subjected to deacetylation amide fragment with obtaining the specified end of the connection, i.e. substituted aniline compounds represented by the General formula (6). In this case, in the General formula (5) R1, R2, R3X and Y have the same definitions as given above.

Specified the deacetylation is preferably carried out using a base due to the stability of a given product.

As the base used in the reaction in stage 4, it should be mentioned, for example, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide and the like is; the alkaline earth metal hydroxide such as barium hydroxide and the like; carbonates such as potassium carbonate, sodium carbonate and the like; and organic amines, such as 1,8-diazabicyclo[5.4.0]undec-7-ene and the like. Of these preferred bases are the hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide and the like.

The number used in stage 4 can be at any level, provided that it does not destroy the formed substituted aniline compound represented by the General formula (6). However, the amount is usually from 0.1 to 30 moles, preferably from 0.5 to 10 moles per mole of 2-(pyrimidine-2-elgeroctober)acetanilide compounds represented by the General formula (5).

The reaction in stage 4 can be performed using a solvent. The solvent used in stage 4, it is not critical, provided that it does not degrade the interaction. In this connection it should be mentioned, for example, aromatic hydrocarbons such as toluene, xylene, chlorobenzene and the like; alcohols such as methanol, ethanol and the like; aprotic polar solvents such as dimethylformamide, dimethylacetamide and the like; solvents of the type of simple ether, such as diethyl ether, tetrahydrofur the Academy of Sciences, dioxane and the like; aliphatic hydrocarbons such as pentane, n-hexane and the like; glycols such as polyethylene glycol (PEG)-400 and the like; and water. The solvents can be used as a single solvent or a mixed solvent of any of the mixture. Can be used any number of solvent, provided that is sufficient stirring of the reaction system, but the number is usually from 0.5 to 20 liters, preferably from 1 to 10 liters per mole of 2-(pyrimidine-2-elgeroctober)acetanilide compounds represented by the General formula (5).

The reaction temperature in stage 4 may be, for example, -15°With up to temperature phlegmy solvent used, but preferably the temperature is from -5°to 100°C.

Time of carrying out the reaction in stage 4 is not a significant factor, however, preferably it ranges from 0.5 hour to 24 hours.

As described previously, any of the reactions of recovery and deacetylation acetanilide compounds represented by the General formula (4)may be carried out first. Therefore, further described in the following order stage (stage 5) deacetylation acetanilide compounds represented by the General formula (4), with the amino compounds represented by the General formula (7), and stage (stage 6) recovery of the amino compounds represented by the General formula (7), with the final product, i.e. substituted aniline compounds represented by the General formula (6).

Stage 5 is the stage of conducting solvolysis of substituted acetanilide compounds represented by the General formula (4), obtained in stage 2, using acid to obtain the amino compounds represented by the General formula (7).

Examples of the acid used in stage 5, can serve as a mineral acid, such as hydrochloric acid, sulfuric acid and the like; a Lewis acid such as boron TRIFLUORIDE and the like; acetic acid, such as acetic acid, triperoxonane acid and the like; sulfonic acids such as p-toluensulfonate and the like; and acidic ion exchange resins such as Amberlist and the like. Preferred acids are hydrochloric acid or sulphuric acid.

Can be used any number of acid used in stage 5, provided that it does not destroy the educated aminosilane represented by the General formula (7), however, the amount of acid is usually from 0.1 to 10 moles, preferably from 0.5 to 5 moles per mole of substituted acetanilide compounds represented by the General formula (4).

The reaction at the stage 5 is carried out in the presence of a solvent. The solvent can serve water and C1-C6 alcohols from straight or branched chain, such as ethanol, methanol and the like. The amount of solvent is usually 1 mole or more per mole of substituted acetanilide compounds represented by the General formula (4), and may be, for example, is usually from 0.1 to 10 liters, preferably from 0.5 to 10 liters per mole of substituted acetanilide compounds represented by the General formula (4). The amount of solvent varies depending on the type and amount of acid used in stage 5, but may be such that the pH of the reaction system becomes approximately 4 or less, preferably 2 or less, more preferably 1 or less.

The reaction in stage 5 may be sufficient when using one of the above solvents. However, the reaction can also be carried out by further adding another solvent.

The solvent, which is used to add to the reaction mixture in stage 5, can be any solvent, provided that it does not weaken the solvolysis reaction in stage 5. In this connection it should be mentioned, for example, aromatic hydrocarbons such as toluene, xylene, chlorobenzene and the like; aprotic polar Rast is oriali, such as dimethylformamide, dimethylacetamide and the like; solvents of the type of simple ether, such as diethyl ether, tetrahydrofuran, dioxane and the like; aliphatic hydrocarbons such as pentane, n-hexane and the like; NITRILES such as acetonitrile and the like; glycols such as polyethylene glycol (PEG)-400 and the like. These solvents may be used as one type of solvent or in the form of a mixture of two or more types of solvents.

When the reaction at the stage 5 is performed with the use of alcohol as a solvent, alcohol can interact with the carbonyl group of a given product and can be formed acetaline connection. In this case, water is added in the presence of acid, or the reaction mixture is poured into water and stirred for a period of time from several minutes to 48 hours, thereby removing the acetal can be readily implemented and specified product can be obtained.

Can be used any number of solvent, provided that the solvent allows sufficient mixing of the reaction system, but the number may be from 0.5 to 5 liters, preferably from 1 to 3 liters per mole of substituted acetanilide compounds represented by the General formula (4).

The reaction temperature in stage 5 m which may be for example, from 0°With up to temperature phlegmy used solvent and is preferably from 0 to 120°C.

Time of carrying out the reaction at the stage 5 is not essential, however, preferably it ranges from 0.5 hour to 24 hours.

Stage 6 represents a stage of recovery obtained above amino compounds represented by the General formula (7), by sodium borohydride to obtain the final product, i.e. substituted aniline compounds represented by the General formula (6). The reaction scheme and the conditions of its implementation are similar to those in stage 3.

Thus obtained end product, i.e. the substituted aniline compound represented by the General formula (6), becomes an important intermediate product in the production of chemicals for agriculture and pharmaceuticals.

In addition, the present invention also provides new compounds. As described previously, hydrazine powered compounds represented by the General formula (2), 2-methoxyethylmercury is a new compound and can be obtained from the corresponding crude aniline for example, according to the method described in the publication Journal of Organic Chemistry, p. 2849 (1972).

In addition, from (pyrimidine-2-yl)-2-propanone compounds represented by the General formula (1), 1-(4,6-dimethoxypyrimidine-2-yl)-2-propane is h, is a new compound and can be obtained from the raw material, such as 2-phenylsulfonyl-4,6-dimethoxypyrimidine or the like, for example, according to the method described in the publication Chemical & Pharmaceutical Bulletin, p. 152 (1982). This connection is tautomers, and all tautomers are included in the present invention.

In addition, the substituted indole compound represented by the General formula (3)is a new compound and can be obtained through stage 1. In this case, in the General formula (3) R1, R2, R3X and Y have the same definitions as given above.

In the following table 1 shows examples of substituted indole compounds represented by the General formula (3). However, the connection according to the present invention is not limited to these examples and includes all of the compounds represented by the General formula (3).

Meanwhile, the symbols shown in table 1, have the following meanings (the same applies to the following tables).

Me: methyl group

Et: ethyl group

MOM: methoxymethyl group

MeO: a methoxy group

EtO: ethoxypropan

i-Pr: isopropyl group

COOMe: methoxycarbonyl group

NO2: nitrogroup

CF3: triptorelin group

NHAc: acetamide group

Table 1
Connection No.XYR1R2R3Melting point (°)
3-1HHOMeHOMe182-184
3-2MeHMeHMe
3-3HMeOMeHOMe145-147
3-4HEtHHH
3-5MeMeOMeNO2OMe
3-6HMeOOMeMeOMe
3-7EtOHOMeCOOMeOMe
3-8HMOMOMeHOMe176-189
3-9ClHOEtHOEt
3-10HFH NHAcH
3-11HCOOHClHCl
3-12COOMeHHMOMH
3-13MeCOOMeHCF3H
3-14ClMeOMeHOMe
3-15i-PrHOMeHOMe
3-16ClMeOMeHOMe179-181
3-17i-PrHOMeHOMe156-158
3-18HEtOMeHOMe90-95

In addition, substituted acetanilides the connection represented by the General formula (4)is a new compound and can be obtained through stage 2. In this case, in the General formula (3) R1, R2, R3X and Y and AC have the same definitions as given above.

In the following table 2 shows the note is ture substituted acetanilides connection represented by the General formula (4).

OEt
Table 2
Connection No.XYR1R2R3Melting point (°)
4-1HHOMeHOMe
4-2MeHMeHMe
4-3HMeOMeHOMe151-153
4-4HEtHHH
4-5MeMeOMeNO2OMe
4-6HMeOOMeMeOMe
4-7EtOHOMeCOOMeOMe
4-8HMOMOMeHOMe147-150
4-9ClHOEtH
4-10HFHNHAcH
4-11HCOOHClHCl
4-12COOMeHHMOMH
4-13MeCOOMeHCF3H
4-14ClMeOMeHOMe
4-15i-PrHOMeHOMe
4-16ClMeOMeHOMe142-144
4-17OMeHOMeHOme136-137
4-18HEtOMeHOme139-142

In addition, 2-(pyrimidine-2-elgeroctober)acetanilide the connection represented by the General formula (5)is a new compound and can be obtained through the stages 3 [or directly from substituted Indus is a high connection, represented by the General formula (3), without the aid of substituted acetanilide compounds represented by the General formula (4)]. In this case, in the General formula (5) R1, R2, R3X and Y and AC have the same definitions as given above.

In the following table 3 shows examples of 2-(pyrimidine-2-elgeroctober)acetanilide compounds represented by the General formula (5). However, the connection according to the present invention is not limited to these examples and includes all of the compounds represented by the General formula (5).

H
Table 3
Connection No.XYR1R2R3Melting point (°)
5-1HHOMeHOme
5-2MeHMeHMe
5-3HMeOMeHOme
5-4HEtOMeHOme143-147
5-5MeMe OMeNO2Ome
5-6HMeOOMeMeOme
5-7EtOHOMeCOOMeOme
5-8HMOMOMeHOme79-82
5-9ClHOEtHOet
5-10HFHNHAcH
5-11HCOOHClHCl
5-12COOMeHHMOMH
5-13MeCOOMeHCF3H
5-14ClMeOMeHOme
5-15i-PrHOMeHOme
5-16ClNOMeOMe121-123
5-17OMeHOMeHOMe122-125

The following is an example of the reaction scheme of obtaining sulfonanilide connection (which may be the herbicide of the substituted aniline compound represented by the General formula (6), which is obtained from the compounds represented by the General formula (1), through the connections of the various General formulas.

As shown in the above reaction scheme, the method according to the present invention and the connection according to the present invention are particularly suitable for the production of sulfonanilide connection, which is used as the effective ingredient of the herbicide.

Next, the method of obtaining the compounds according to the present invention is described more specifically by way of examples. In the examples, the refractive index n20Dindicates that the refractive index was measured at 20°using the sodium D line. Gas chromatography was performed using column G-250 (40 m) [the company's product (Zai) Depending Busshitsu Hyoka Kenkyu Kiko (before Kagakuhin Kensa Kyokai). High-performance liquid chromatography was performed using a column YMC-A312 (product K.K. YMC), and as the eluent used is Wali mixture of acetonitrile/0.05% solution of phosphoric acid.

Example 1

Getting 2-ethoxymethyleneamino

50 ml of concentrated hydrochloric acid was dissolved 6,86 g (50 mmol) 2-methoxyethylamine. The solution was cooled to -10°C. in Addition, to the solution was added dropwise a solution of sodium nitrite (4,14 g, 60 mmol)dissolved in water (50 ml)while the temperature was maintained between -10°0°C. Then was added dropwise a solution to 44.6 g (235 mmol) douglasthe tin, dissolved in concentrated hydrochloric acid (50 ml), at the above temperature for 1 hour. After adding the solution dropwise to the stirring was performed with a gradual temperature increase to approximately 20°C. Then was added dropwise a 10% aqueous solution of sodium hydroxide to achieve a pH of 14, after which it was carried out by extraction with toluene. Toluene layer was washed with water and concentrated under reduced pressure using a rotary evaporator, with the receipt of 5.40 g (35.5 mmol) of liquid 2-ethoxymethyleneamino. Yield: 71%.

MS m/e 152 (M+)

NMR (CDCl3/TMS), δ (ppm):

of 3.8 (s, 3H), of 4.46 (s, 2H), 7.1 to 7.4 (m, 7H)

IR (NaCl plate, cm-1): 3350 (NH)

Example 2

Obtaining 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone

In a reactor were placed 16.0 g (0.4 mol) of 60% sodium hydride and 400 ml of THF and 43.6 g (0.2 mol) of 4,6-dimethoxy-2-methanesulfonyl is amidine. The contents of the reactor were heated to 30°C. in Addition, the reactor was added dropwise to 39.4 g (of 0.68 mol) of acetone, followed by conducting the reaction for 2 hours. Upon completion of the reaction was added 350 ml of water and extraction was performed with 500 ml of ethyl acetate. An ethyl acetate layer was concentrated. The concentrate was subjected to distillation under reduced pressure to obtain 8.8 g (of 44.9 mmol) 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone. The refractive index n20D: 1,5181.

MS m/e: 196 (M+)

NMR (CDCl3/TMS), δ (ppm):

2,03 (C), and 2.26 (C), 3,86 (C), 3,91 (C, 6N), of 5.40 (C)5,73 (C)5,91 (s, 1H).

Example 3 (stage 1)

Obtaining 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-ethylindole

The reactor was loaded 2.4 g (12.2 mmol) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone, 1.7 g (9,98 mmol) of the hydrochloride of 2-ethylphenethylamine, 1.4 g (10.2 mmol) of zinc chloride and 10 ml of toluene, followed by boiling under reflux for 2 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature. In addition, added water and ethyl acetate and the phases were separated. An ethyl acetate layer was concentrated. The concentrate was subjected to separation using column chromatography on silica gel (solvent for separation: a mixture of n-hexane/ethyl acetate) to obtain 2.38 g (8,01 mmol) 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-ethylindole. Yield: 80.3 per cent. Melting point: from 90,3 on the 94,8° C.

MS m/e 297 (M+)

NMR (CDCl3/TMS), δ (ppm):

to 1.38 (t, 3H), 2,87 (kV, 2H), 2,96 (s, 3H), 4,08 (C, 6N), to 5.85 (s, 1H), 7,03 (d, 1H), 7,18 (t, 1H), 8,18 (broad s, 1H), to 8.57 (d, 1H).

Example 4 (stage 2)

Getting 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethylacetamide

The reactor was loaded 0.7 g (2.4 mmol) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-ethylindole and 10 ml of ethyl acetate. Then let the ozone at a temperature of from 0°to 10°C for 2 hours. Upon completion of the reaction, the reaction mixture was heated to room temperature and concentrated. The result was obtained 0.75 g (2.3 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethylacetamide, Yield: 95%. Melting point: from 139,3 to 142,3°C.

MS m/e 329 (M+)

NMR (CDCl3/TMS), δ (ppm):

of 1.25 (t, 3H), 2,17 (s, 3H), 2,69 (kV, 2H), 3,95 (C, 6N), 6,16 (s, 1H), 7.2 to 7.3 (m, 1H), from 7.4 to 7.6 (m, 2H), of 8.95 (broad s, 1H).

Example 5 (stage 3)

Getting 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethylacetamide

In a reactor were placed 1.0 g (3.03 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethylacetamide and 20 ml of ethanol. The contents of the reactor were cooled to 5°With or below. Then added to 0.13 g (3.65 mmol) of sodium borohydride and stirred at the same temperature for 1 hour. Then, the reaction mixture was heated to room temperature. Upon completion of the reaction was added an aqueous solution of ammonium chloride and spent extra is tion with ethyl acetate. The organic layer was concentrated to obtain 0,82 g (2.48 mmol) of 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethylacetamide. Yield: 82%. Melting point: from 143 to 147°C.

MS m/e 331 (M+)

NMR (CDCl3/TMS), δ (ppm):

to 1.24 (t, 3H), 2,22 (s, 3H), of 2.64 (q, 2H), 3,97 (C, 6N), 4,88 (d, 1H), of 5.89 (d, 1H), 5,95 (s, 1H), 7.2 to 7.5 (m, 3H), 9,25 (broad s, 1H).

Example 6 (stage 4)

Getting 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethylaniline

In a reactor were placed 0.1 g (0.30 mmol) of 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethylacetamide, 2 ml methanol and 2 ml of water. Stirring was carried out at 70°C for 6 hours. Upon completion of the reaction conducted high-performance liquid chromatography. The result was obtained 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethylaniline with the release of 65%.

Example 7 (step 1)

Obtaining 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-methoxymethanol

The reactor was loaded 6.2 g (of 31.6 mmol) 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone, 4.8 g (to 31.5 mmol) of 2-ethoxymethyleneamino, 4,76 g (34,9 mmol) of zinc chloride and 60 ml of toluene. The reaction mixture is boiled under reflux for 2 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature. Then added water and ethyl acetate and the phases were separated. An ethyl acetate layer was concentrated. Formed crystals were washed of diisopropyl the m ether with the receipt of 4.57 g (14.6 mmol) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-methoxymethanol. Yield: 46%.

MS m/e 313 (M+)

NMR (CDCl3/TMS), δ (ppm):

2,95 (s, 3H), 3,34 (s, 3H), 4,06 (C, 6N), 4,74 (s, 2H), of 5.81 (s, 1H), 7.0 to 7.1 (m, 3H), 8,65 (d, 1H).

The obtained 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-methoxymethanol can be used in the reaction in stage 2 on the basis of example 4.

Example 8 (stage 2)

Getting 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethoxymethyleneamino

In a reactor were placed 1.0 g (31.9 per mmol) 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-methoxymethanol and 40 ml of ethyl acetate. To this mixture was allowed ozone at a temperature of from 0°to 10°C for 4 hours. Upon completion of the reaction the contents of the reactor were heated to room temperature and concentrated. The residue was subjected to column chromatography on silica gel (solvent for separation: a mixture of n-hexane/ethyl acetate) to obtain 0.40 g (11.6 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethoxymethyleneamino. Melting point: from 147 to 150°C. Output: 36,4%.

MS m/e 345 (M+)

NMR (CDCl3/TMS), δ (ppm):

to 2.13 (s, 3H), 3,39 (s, 3H), of 3.94 (s, 6N), 4,47 (s, 2H). x 6.15 (s, 1H), 7,26 (t, 1H), 7,60 (d, 2H), 7,63 (d, 1H), 9,29 (broad, 1H).

Obtained 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethoxymethyleneamino can be used in the reaction in stage 3 according to example 5.

Example 9 (continuous procedure at stage 3 and stage 4 in the same reactor)

Getting 2-(4,6-d is methoxypyridine-2-ylcarbonyl)-6-ethoxymethyleneamino

In a reactor were placed 1.0 g (2.9 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethoxymethyleneamino and 20 ml of ethanol, followed by cooling to 5°With or below. Then the reactor was placed 0.5 g (13.5 mmol) of sodium borohydride. Mixing was performed at the same temperature for 1 hour. Then the mixture was heated to room temperature. Upon completion of the reaction was added an aqueous solution of ammonium chloride and extraction was performed with ethyl acetate. The organic layer was concentrated. To the residue was added 20 ml of water and 0.4 g (7.1 mmol) of potassium hydroxide, followed by stirring at 70°C for 2 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and was added 50 ml of ethyl acetate and 50 ml of water to perform the extraction. The organic layer was concentrated and the concentrate was subjected to column chromatography on silica gel (solvent for separation: a mixture of n-hexane/ethyl acetate) to obtain 0.35 g (1.48 mmol) of 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethoxymethyleneamino. Yield: 51%.

Example 10 (stage 1)

Obtaining 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole

In 10 ml of toluene was dissolved 1,61 g (8.2 mmol) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone and 1.08 g (10 mmol) of phenylhydrazine. To the solution was added to 1.36 g (10 mmol) of zinc chloride, followed by boiling under reflux for 1 hour. actionnow the mixture was left to cool and then added ethyl acetate and water, to dissolve the entire reaction mixture. The oily layer was washed with water, separated and dried over the Glauber salt. Educated oily layer was concentrated under reduced pressure to obtain solid orange color. The solid is recrystallized from methanol with the receipt of 1.37 g (5.1 mmol) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole) are studied. Yield: 62%. Melting point: 182 to 184°C.

MS m/e 269 (M+)

NMR (CDCl3/TMS), δ (ppm):

to 2.94 (s, 3H), 4,06 (C, 6N), of 5.81 (s, 1H), and 7.1 (m, 2H), and 7.3 (m, 1H), 8,7 (m, 1H)

IR (KBr, cm-1): 3490 (NH), 1570

The obtained 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindol can be used in the reaction in stage 2 according to example 4 or example 8.

Example 11 (stage 2)

Getting 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide

The reactor was loaded 0.8 g (3.0 mmol) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole, 30 ml of acetone and 8 ml of water. Then added 1.5 g (9.9 mmol) of potassium permanganate and to 2.29 g (10,7 mmol) periodate sodium and interaction were carried out at room temperature for 12 hours. After the reaction mixture was filtered. The filtrate was subjected to extraction with ethyl acetate. An ethyl acetate layer was concentrated. The residue was washed with isopropyl ether to obtain 0,57 g (1.9 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide. Yield: 63%.

MS m/e 301 (M+)

NMR (CDClsub> 3/TMS), δ (ppm):

of 2.28 (s, 3H), 3.96 points (C, 6N), 6,16 (s, 1H), 7,06 (t, 1H), 7,27 (broad, 1H), to 7.59 (d, 1H), 8,78 (d, 1H)

IR (KBr, cm-1): 3270 (NH), 1700, 1660 (C=O)

Obtained 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide can be used in the reaction in stage 3 according to example 5 or example 9.

Example 12 (stage 1)

Obtaining 3-(4,6-dimethoxypyrimidine-2-yl)-2,7-dimethylindole

In 20 ml of toluene was dissolved 0,77 g (3.9 mmol) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone, and 0.69 g (4.3 mmol) of the hydrochloride of 2-methylphenylhydrazine. To the solution was added 0.64 g (4.7 mmol) of zinc chloride, followed by boiling under reflux for 2 hours. The reaction mixture was left to cool and then added ethyl acetate and water to dissolve all of the reaction mixture. The oily layer was washed with water, separated and dried over the Glauber salt. The resulting oily layer was concentrated under reduced pressure using a rotary evaporator, to obtain the solid orange color. The solid was treated with a mixture of ethyl acetate/n-hexane to obtain 0,38 g (of 1.34 mmol) 3-(4,6-dimethoxypyrimidine-2-yl)-2,7-dimethylindole. Yield: 34%. Melting point: 145-147°C.

MS m/e 283 (M+)

NMR (CDCl3/TMS), δ (ppm):

2,47 (s, 3H), 2,90 (s, 3H), of 4.05 (s, 6N), of 5.83 (s, 1H), 6,98 (d, 1H), 7,13 (t, 1H), 8,15 (d, 1H), and 8.50 (d, 1H)

IR (cm-1): 3350 (NH)

The obtained 3-(4,6-Dimitar apyrimidine-2-yl)-2,7-dimethylindole can be used in the reaction in stage 2 according to example 4, or example 8 or example 12.

Example 13 (stage 2)

Getting 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide

In a reactor were placed 1.0 g (3.7 mmol) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole, 30 ml of acetone and 15 ml of water. To the reactor was added 3.0 g (19 mmol) of potassium permanganate and the interaction was carried out at room temperature for 12 hours. Upon completion of the reaction, the reaction mixture was subjected to gas chromatography. The result was obtained 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide with yield 74%, based on its share of the total area of the peaks.

Example 14 (stage 2)

Getting 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-methylacetanilide

In a reactor were placed 283 mg (1.0 mmol) 3-(4,6-dimethoxypyrimidine-2-yl)-2,7-dimethylindole and 15 ml of acetone. To the reactor was added 790 mg (5.0 mmol) of potassium permanganate and 214 mg (1.0 mmol) of periodate sodium and interaction was carried out for 12 hours. Upon completion of the reaction, the reaction mixture was filtered. The filtrate was extracted with ethyl acetate. An ethyl acetate layer was concentrated. The residue was washed with isopropyl ether to obtain 80 mg (0.25 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-methylacetanilide. Yield: 25%. Melting point: 151 to 153°C.

MS m/e 315 (M+)

NMR (CDCl3/TMS), δ (ppm):

2,47 (s, 3H), 2,90 (s, 3H), of 4.05 (s, 6N), of 5.83 (s, 1H), 6,98 (d, 1H), 7,13 (t, 1H), 8,15 (broad, 1H), and 8.50 (d, 1H).

Obtained 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-methylacetanilide can be used in the reaction in stage 3 according to example 5 or example 9.

Example 15 (stage 2)

Getting 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide

In a reactor were placed 0.27 g (10 mmol) 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole and 10 ml of ethyl acetate. Then let the ozone at a temperature of from 0°to 10°C for 3 hours. Upon completion of the reaction, the reaction mixture was heated to room temperature and concentrated. The residue was subjected to gas chromatography. The result was obtained 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide with the release of 88%based on its share of the total area of the peaks.

Example 16 (step 2)

Getting 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-methylacetanilide

In a reactor were placed 3-(4,6-dimethoxypyrimidine-2-yl)-2,7-dimethylindole and ethyl acetate. Then let the ozone at a temperature of from 0°to 10°C for 3 hours. Upon completion of the reaction, the reaction mixture was heated to room temperature and concentrated. The residue was subjected to gas chromatography. The result was obtained 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-methylacetanilide with the release of 63%based on its share of the total area of the peaks.

Example 17 (stage 2)

Getting 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethylacetamide

In a reactor were placed 0.5 g (1.7 mmol) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-ethylindole, 10 ml of acetone and 5 ml of water. To the reactor was added potassium permanganate and periodate sodium and mixed is at room temperature for communicating. The reaction mixture was subjected to gas chromatography. The result was obtained 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethylacetamide with the release of 47%, based on its share of the total area of the peaks.

Example 18 (stage 3)

Getting 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethoxymethyleneamino

In a reactor were placed 1.7 g (4.9 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethoxymethyleneamino and 20 ml of ethanol. The contents of the reactor were cooled to 5°With or below. To the reactor was added 0.4 g (about 10.8 mmol) of sodium borohydride and the mixture was stirred at the same temperature for 1 hour to effect the interaction. Then the mixture was heated to room temperature. Upon completion of the reaction was added an aqueous solution of ammonium chloride and was carried out by extraction with ethyl acetate. The organic layer was concentrated to obtain 1,32 g (3.8 mmol) of 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethoxymethyleneamino. Yield: 78%. Melting point: from 79 to 82°C.

MS m/e 347 (M+)

NMR (CDCl3/TMS), δ (ppm):

2,24 (s, 3H), 3,38 (s, 3H), of 3.97 (s, 6N), of 4.45 (q, 2H), 4,87 (d, 1H), 5,90 (d, 1H), 7.2 to 7.3 (m, 1H), 7,46 (d, 2H), 9,41 (broad s, 1H).

Obtained 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethoxymethyleneamino can be used in the reaction in stage 4 according to example 6.

Example 19 (continuous procedure in stage 2 and stage 3 in one and the same reactor)

Getting 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethylacetamide

In a reactor were placed 1.0 g (3,37 mmol) 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-ethylindole and 20 ml of ethyl acetate. The contents of the reactor were cooled to 5°With or below. Then let the ozone at a temperature of from 0°to 10°C for 2 hours. Upon completion of the reaction was added to 20 ml of ethanol. In addition, there was added 0.25 g (6,76 mmol) of sodium borohydride and stirred for 1 hour. Upon completion of the reaction, the reaction mixture was heated to room temperature. For extraction was added an aqueous solution of ammonium chloride and ethyl acetate. The organic layer was concentrated and the concentrate was subjected to column chromatography on silica gel (solvent for separation: a mixture of n-hexane/ethyl acetate) to obtain 0.26 g (0,79 mmol) of 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethylacetamide. Output: 27,4%.

Obtained 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethylacetamide can be used in the reaction in stage 4 according to example 6.

Example 20 (continuous procedure at stage 3 and stage 4 in the same reactor)

Getting 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethoxymethyleneamino

In a reactor were placed 1.0 g (2.9 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethoxymethyleneamino obtained in accordance with example 8, and 20 ml of ethane is La. The contents of the reactor were cooled to 5°With or below. To the reactor was added 0.5 g (13.5 mmol) of sodium borohydride, followed by stirring at the same temperature for 1 hour. Then the mixture was heated to room temperature. Upon completion of the reaction was added an aqueous solution of ammonium chloride and was carried out by extraction with ethyl acetate. The organic layer was concentrated. To the residue was added 20 ml of methanol and 1.5 g (26.8 mmol) of potassium hydroxide. The mixture was stirred at 70°C for 2 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and was added 50 ml of ethyl acetate and 50 ml of water for extraction. The organic layer was concentrated. The concentrate was subjected to column chromatography on silica gel (solvent for separation: a mixture of n-hexane/ethyl acetate) to obtain 0.24 g (0,79 mmol) of 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethoxymethyleneamino. Output: 27,1%.

NMR (CDCl3/TMS), δ (ppm):

and 3.31 (s, 3H), of 3.94 (s, 6N), 4,51 (DD, 2H), of 4.66 (broad s, 1H), further 5.15 (broad s, 2H), of 5.84 (s, 1H), to 5.93 (s, 1H), of 6.71 (t, 1H), 6.7 to 6.8 (m, 1H), 6.9 to 7.1 (m, 1H), 7.2 to 7.3 (m, 1H).

Example 21 (continuous procedure in stage 2 and stage 3 in the same reactor)

Getting 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethoxymethyleneamino

In a reactor were placed 1.0 g (3,19 mmol) 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-meth is cimetidine and 20 ml of ethyl acetate. The contents of the reactor were cooled to 5°With or below. Then let the ozone at a temperature of from 0°to 10°C for 3 hours. Upon completion of the reaction was added to 20 ml of ethanol. In addition, there was added 0.5 g (13.5 mmol) of sodium borohydride, followed by stirring for 1 hour. Upon completion of the reaction, the reaction mixture was heated to room temperature and was added an aqueous solution of ammonium chloride and ethyl acetate for extraction. The organic layer was concentrated. The concentrate was subjected to column chromatography to obtain 0.18 g (0.52 mmol) of 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethoxymethyleneamino. Output: 16.3 per cent.

Obtained 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethoxymethyleneamino can be used in the reaction in stage 4 in accordance with example 6.

Example 22 (stage 5)

Getting 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)aniline

In a reactor were placed 0,57 g (1.9 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide, 10 ml of methanol and 5 ml of 6 N hydrochloric acid followed by boiling under reflux for 1 hour. Upon completion of the reaction, the reaction mixture was podslushivaet sodium hydroxide, after which extraction was performed with ethyl acetate. An ethyl acetate layer was concentrated. The residue was subjected to gas chromatography. The result was proof is on the formation of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)aniline. Transformation: 100% (based on its share of the total area of peaks in gas chromatography). Example 23 (stage 5)

Getting 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethoxymethyleneamino

The reactor was mixed with 50 ml of methanol and 10 ml of concentrated sulfuric acid. To the reactor was added 1.0 g (2.9 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethoxymethyleneamino followed by boiling under reflux at 65°C for 4 hours. Then the reaction mixture was left to cool to room temperature. Then add 50 ml of water and stirred at a temperature of approximately 20°With during the night. Upon completion of the reaction, the reaction mixture was poured into water and extraction was performed with ethyl acetate. An ethyl acetate layer was concentrated. The residue was subjected to column chromatography with the receipt of 0.30 g (1 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-ethoxymethyleneamino. Yield: 34%.

Example 24 (continuous procedure in stage 2 and stage 5 in the same reactor)

Getting 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)aniline

In a reactor were placed 0,60 g (22 mmol) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole and 20 ml of ethyl acetate. To the reactor was allowed ozone at a temperature of from 0°to 10°C for 4 hours. To confirm the disappearance of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole and completion of the reaction was performed tone is osoyou chromatography. Then the reaction mixture was heated to room temperature and concentrated. To the concentrate was added 20 ml of methanol and 5 ml of 6 N hydrochloric acid and heated under reflux for 1 hour. Upon completion of the reaction, the reaction mixture was cooled to room temperature. Then was added 100 ml of water. The mixture was podslushivaet aqueous solution of sodium hydroxide and extraction was performed with ethyl acetate. The organic layer was concentrated. The concentrate was subjected to column chromatography to obtain 0.26 g (10 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)aniline. Yield: 46%.

MS m/e 259 (M+)

NMR (CDCl3/TMS), δ (ppm):

to 3.99 (s, 6N), 6,18 (s, 1H), 6.42 per (broad, 2H), 6.5 to 6.6 (m, 1H). 6,70 (d, 1H), 7.2 to 7.3 (m, 1H). 7,40 (d, 1H).

Example 25 (stage 1)

Getting 5-chloro-3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole

To 80 ml of toluene was added 8.0 g (40 mmol) 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone and 7.9 g (44 mmol) of the hydrochloride of 4-chlorophenylhydrazone. To the mixture was added 6,54 g (48 mmol) of zinc chloride. The mixture is then boiled under reflux for 2 hours. The reaction mixture was left to cool. Then added ethyl acetate and water to dissolve all of the reaction mixture. The organic layer was washed with water, separated and dried over the Glauber salt. The separated organic layer was concentrated under reduced pressure, the using a rotary evaporator, to obtain 10.2 g (33,7 mmol) 5-chloro-3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole) are studied. Yield: 84%. Melting point: 179 to 181°C.

MS m/e 303 (M+) NMR (CDCl3/TMS), δ (ppm):

only 2.91 (s, 3H), Android 4.04 (s, 6N), of 5.82 (s, 1H), and 7.1 (m, 1H), and 7.3 (m, 1H), 8,7 (m, 1H)

IR (KBr, cm-1): 3510 (NH), 1580

Example 26 (stage 2)

Getting 4-chloro-2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide

In a reactor were placed 6,1 g (20 mmol) 5-chloro-3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole, 200 ml of acetone and 100 ml of water. To the reactor was added 19,0 g (120 mmol) of potassium permanganate and 8.6 g (40 mmol) Periodica sodium. The reaction was carried out at room temperature for 16 hours. Upon termination of the reaction were filtered. The filtrate was extracted with ethyl acetate. An ethyl acetate layer was koncentrirebuli. The concentrate was purified column chromatography on silica gel (mixture of n-hexane/ethyl acetate = 4/1) to obtain 1.8 g (5.4 mmol) of 4-chloro-2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide. Yield: 27%. Melting point: from 142 to 144°C.

MS m/e 335 (M+)

NMR (CDCl3/TMS), δ (ppm):

of 2.27 (s, 3H), 3,98 (C, 6N), of 6.20 (s, 1H), 7,56 (kV, 1H), 7,69 (m, 1H), 8,76 (d, 1H)

IR (KBr, cm-1): 3320 (NH), 1700, 1660 (C=O)

Example 27 (stage 3)

Getting 4-chloro-2-(4,6-dimethoxypyrimidine-2-elgeroctober)acetanilide

In a reactor were placed 1,00 g (3.0 mmol) 4-chloro-2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide and 20 ml of ethanol. The content is imoe reactor was cooled to 5° C or lower. To the reactor was added 0.25 g (6.6 mmol) of sodium borohydride. The mixture was stirred at the same temperature for 1 hour. Then the temperature was raised to room temperature. Upon completion of the reaction was added an aqueous solution of ammonium chloride and extraction was performed with ethyl acetate. The organic layer was concentrated. The concentrate was purified column chromatography on silica gel (mixture of n-hexane/ethyl acetate = 1/1) to obtain the 0,69 g (2.0 mmol) of 4-chloro-2-(4,6-dimethoxypyrimidine-2-elgeroctober) acetanilide. Yield: 68%. Melting point: 121 to 123°C.

NMR (CDCl3/TMS), δ (ppm):

2,22 (s, 3H), 3,98 (C, 6N), 4,89 (d, 1H), of 5.81 (d, 1H), of 5.89 (s, 1H), 7,2 (m, 1H), 7.5 (m, 1H), and 7.8 (d, 1H), 9,72 (broad, 1H)

IR (KBr, cm-1): 3430 (NH), 3300 (OH), 1700, 1600 (C=O).

Example 28 (stage 1)

Obtaining 3-(4,6-dimethoxypyrimidine-2-yl)-5-methoxy-2-methylindole

To 80 ml of toluene was added 8.0 g (40 mmol) 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone and 7.7 g (44 mmol) of the hydrochloride of 4-methoxyphenylhydrazine. To the mixture was added 6.0 g (44 mmol) of zinc chloride. Then the reaction mixture is boiled under reflux for 2 hours. The reaction mixture was left to cool. To the reaction mixture were added ethyl acetate and water to dissolve all of the reaction mixture. The oily layer was washed with water, separated and dried over the Glauber salt. The separated organic layer was concentrated the ri reduced pressure, using a rotary evaporator, to obtain 8.0 g (to 26.7 mmol) of 3-(4,6-dimethoxypyrimidine-2-yl)-5-methoxy-2-methylindole in a solid orange color. Yield: 67%. In addition, I conducted recrystallization from toluene. Melting point: 182 to 184°C.

MS m/e 299 (M+)

NMR (CDCl3/TMS), δ (ppm):

2,87 (s, 3H). the 3.89 (s, 3H), 4,07 (C, 6N), of 5.84 (s, 1H), 6,9 (m, 1H), 7,2 (m, 1H). 8,2 (broad, 1H), and 8.7 (s, 1H).

IR (cm-1): 3340 (NH), 1570.

Example 29 (stage 2)

Getting 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-4-methoxyacetanilide

In a reactor were placed 6.0 g (20 mmol) 3-(4,6-dimethoxypyrimidine-2-yl)-5-methoxy-2-methylindole, 200 ml of acetone and 100 ml of water. To the reactor was added 19,0 g (120 mmol) of potassium permanganate and 8.6 g (40 mmol) of periodate sodium. The interaction was carried out at room temperature for 16 hours. Upon termination of the reaction were filtered. The filtrate was extracted with ethyl acetate. An ethyl acetate layer was concentrated. The residue was purified column chromatography on silica gel (mixture of n-hexane/ethyl acetate = 4/1) with poluchenii 0.9 g (2.7 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-4-methoxyacetanilide. Yield: 14%. MS m/e 331 (M+)

NMR (CDCl3/TMS), δ (ppm):

of 2.25 (s, 3H), 3,74 (s, 3H), 3.96 points (C, 6N), 6,17 (s, 1H), from 7.1 to 7.2 (m, 2H), and 8.7 (d, 1H)

IR (cm-1): 3250 (NH), 1690, 1650 (C=O).

Example 30 (stage 3)

Getting 2-(4,6-dimethoxypyrimidine-2-algidras is methyl)-4-methoxyacetanilide

In a reactor were placed 0.66 g (2.0 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-4-methoxyacetanilide and 10 ml of ethanol. The contents of the reactor were cooled to 5°With or below. To the reactor was added 0.17 g (4.4 mmol) of sodium borohydride. The mixture was stirred at the same temperature for 1 hour. Then the mixture was heated to room temperature. Upon completion of the reaction was added an aqueous solution of ammonium chloride and extraction was performed with ethyl acetate. The organic layer was concentrated. The concentrate was purified column chromatography on silica gel (mixture of n-hexane/ethyl acetate = 2/3) to obtain 0.55 g (1.6 mmol) of 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-4-methoxyacetanilide. Yield: 82%. Melting point: 122°C to 125°C.

NMR (CDCl3/TMS), δ (ppm):

of 2.21 (s, 3H), of 3.80 (s, 3H), of 3.97 (s, 6N), to 4.87 (d, 1H), of 5.84 (d, 1H), 5,96 (s, 1H), 6,8 (m, 1H), 7,07 (d, 1H), 7,69 (kV, 1H), 9,49 (broad, 1H).

IR (cm-1): 3470 (NH), 3250 (OH), 1670, 1600 (C=O).

Example 31 (stage 6)

Getting 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethoxymethyleneamino

In a reactor were placed 1.0 g (0,0033 mol) of 2-(4,6-dimethoxypyrimidine-2-yl)carbonyl-6-ethoxymethyleneamino and 50 ml of ethanol. To the reactor was added 0.125 g (0,0033 mol) of sodium borohydride while cooling with ice (10°or lower). The mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, to the reaction mixture was added saturated aq is th solution of ammonium chloride for acidification of the mixture. Then added ethyl acetate to effect the extraction. The organic layer was washed with water and saturated aqueous sodium chloride, in that order. Then the organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 0,91 g (0,0030 mol) of 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethoxymethyleneamino. Yield: 90%. Obtained 2-(4,6-dimethoxypyrimidine-2-elgeroctober)-6-ethoxymethyleneamino were subjected to instrumental analysis and showed that the data were consistent with data for compounds described in the examples.

Industrial application

According to the present invention is obtained 2-(pyrimidine-2-elgeroctober)acetanilide connection, which is an important intermediate product for sulfonanilide of the compounds exhibiting excellent herbicide action, and also presents the industrial method of obtaining substituted aniline compounds using the above acetanilide compounds as an intermediate product.

1. The method of obtaining substituted aniline compounds represented by the following General formula (6):

where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, ka is boxallow group, alkoxycarbonyl group, alkylcarboxylic group, a nitrogroup, a halogen atom or a hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or a halogen atom,

characterized in that the method comprises the oxidation of substituted indole compounds represented by the following General formula (3):

where R1, R2, R3, X and Y have the same definitions as given above, resulting in the disclosure of the indole ring with getting acetanilide compounds represented by the following General formula (4):

where R1, R2and R3, X and Y have the same definitions as given above; AC is acetyl group, and processing the connection through recovery and deacetylation, provided that at least one of R1, R2and R3means the nitrogroup, and the reduction of carbonyl groups are using as a reducing agent NaBH4.

2. The method according to claim 1, characterized in that the first process, the compounds of formula (4) by reduction with obtaining 2-(pyrimidine-2-alhydrogel the Teal)-acetanilide connection represented by the following General formula (5):

and consistently spend deacetylation.

3. The method according to claim 2, characterized in that the recovery of the compounds of formula (4) may carry out without highlighting.

4. The method according to claim 1, characterized in that the first conduct the deacetylation of compounds of formula (4) obtaining the amino compounds represented by the following General formula (7):

where R1, R2, R3, X and Y have the same definitions as given above, and then recover.

5. The method according to any one of claims 1 to 4, wherein the restoring is performed with sodium borohydride.

6. The method according to any one of claims 1 to 4, where the substituted indole compound represented by the following General formula (3):

where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl, alkoxycarbonyl group, alkylcarboxylic group, a nitrogroup, a halogen atom or a hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or a halogen atom,

receive interaction (pyrimidine-2-yl)-2-propranololo compounds represented by the following General formula (1):

where R1, R2and R3have the same definitions as given above,

with hydrazine powered by the connection represented by the following General formula (2):

where X and Y have the same definitions as given above,

in the presence of acid.

7. The method of obtaining the amino compounds represented by the following General formula (7):

where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitrogroup, a halogen atom or a hydrogen atom; and X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or a halogen atom,

characterized in that the method comprises the oxidation of substituted indole compounds represented by the following General formula (3):

where R1, R2, R3, X and Y have the same op is edeline, as given above, resulting in the disclosure of the indole ring with getting acetanilide compounds represented by the following General formula (4):

where R1, R2, R3, X and Y have the same definitions as given above; AC is acetyl group,

and deacetylation this connection.

8. The method of obtaining 2-(pyrimidine-2-elgeroctober)-acetanilide compounds represented by the following General formula (5):

where R1, R2and R3each independently mean alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group, alkylcarboxylic group, a nitrogroup, a halogen atom or a hydrogen atom; X and Y each independently means a hydrogen atom, alkyl group, alkoxygroup, alkoxyalkyl group, halogenation group, carboxyl group, alkoxycarbonyl group or a halogen atom; AC is acetyl group, characterized in that the method comprises the oxidation of substituted indole compounds represented by the following General formula (3):

where R1, R2, R3, X and Y have the same definitions as given above,

the actuator is suitable for the disclosure of the indole ring with getting acetanilide connection represented by the following General formula (4):

where R1, R2, R3X, Y and AC have the same definitions as given above,

and restore this connection, provided that at least one of R1, R2and R3mean the nitrogroup, and the reduction of carbonyl groups are using as a reducing agent NaBH4.

9. The method according to claim 8, characterized in that the recovery of the compounds of formula (4) may carry out without highlighting.

10. The method of claim 8, where the recovery is performed with sodium borohydride.

11. The method according to claim 8, characterized in that the substituted indole compound represented by the General formula (3)produced by the interaction (pyrimidine-2-yl)-2-propranololo connection with hydrazine powered compound in the presence of acid.

12. The method according to claim 1, characterized in that acetanilide connection with General formula (4) is obtained by oxidation of substituted indole compounds represented by the following General formula (3):

where R1, R2, R3, X and Y have the same definitions as given above,

leading to the disclosure of the indole ring.

13. The method according to claim 4, characterized in that aminosilane represented by the General formula (7), p is obtain by deacetylation acetanilide connection represented by the following formula (4):

where R1, R2, R3, X and Y have the same definitions as given above; AC means acetyl group.

14. The method according to claim 2, characterized in that 2-(pyrimidine-2-elgeroctober)acetanilide the connection represented by the General formula (5),

receive by restoring acetanilide compounds represented by the following General formula (4):

where R1, R2, R3X, Y and AC have the same definitions as given above.

15. The method according to 14, where the recovery is performed with sodium borohydride.

16. The method according to claim 2 to 4, characterized in that the substituted aniline compound represented by the General formula (6) is obtained by deacetylation of 2-(pyrimidine-2-elgeroctober)acetanilide compounds represented by the following General formula (5):

where R1, R2, R3, X and Y have the same definitions as given above, AC is an acetyl group.

17. 2-Methoxyethylmercury formula

18. 1-(4,6-Dimethoxypyrimidine-2-yl)-2-propanone of the formula

19. Substituted indole compounds is s, represented by the following General formula (3):

where R1, R2and R3each independently mean C1-6alkyl group, a C1-6alkoxygroup,1-6alkoxyl1-6alkyl group, a C1-6halogenating group, a carboxyl group, a C1-6alkoxycarbonyl group, C1-6alkylcarboxylic group, a nitrogroup, a halogen atom or a hydrogen atom; X and Y each independently means a hydrogen atom, a C1-6alkyl group, a C1-6alkoxygroup,1-6alkoxyl1-6alkyl group, a C1-6halogenating group, a carboxyl group, a C1-6alkoxycarbonyl group or halogen atom.

20. Substituted acetanilides the connection represented by the following General formula (4):

where R1, R2and R3each independently mean C1-6alkyl group, a C1-6alkoxygroup, C1-6alkoxyalkyl group, Halogens1-6alkyl group, a carboxyl group, a C1-6alkoxycarbonyl group1-6alkylcarboxylic group, a nitrogroup, a halogen atom or a hydrogen atom; and X and Y each independently means a hydrogen atom, a C1-6alkyl group, a C1-6alkoxygroup,1-6alkoxyl1-6alkyl group, a C1-6 halogenating group, a carboxyl group, a C1-6alkoxycarbonyl group or a halogen atom; AC is acetyl group, provided that when R1, R2and R3represent hydrogen, X is a chlorine atom.

21. 2-(Pyrimidine-2-elgeroctober)acetanilide connection (5):

where R1, R2and R3each independently mean C1-6alkyl group, a C1-6alkoxygroup, C1-6alkoxyalkyl group, C1-6halogenating group, a carboxyl group, a C1-6alkoxycarbonyl group, C1-6alkylcarboxylic group, a nitrogroup, a halogen atom or a hydrogen atom; and X and Y each independently means a hydrogen atom, a C1-6alkyl group, a C1-6alkoxygroup,1-6alkoxyl1-6alkyl group, a C1-6halogenating group, a carboxyl group, a C1-6alkoxycarbonyl group or a halogen atom; AC is acetyl group, provided that when R1, R2and R3represent hydrogen, X is a chlorine atom.

Priority items:

17.10.2000 - on claims 4-7, 11-13, 16, 18-21;

09.02.2001 - according to claim 2, 3, 8-10, 15, 17;

17.10.2000 and 09.02.2001 apply equally to claim 1.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a novel method for synthesis of functionally substituted fullerenes of the general formula (I): Method involves interaction of fullerene[60] with 1H-1,2,3-benzotriazol-1-N,N-dimethylmethaneamine in the presence of Cp2TiCl2 as a catalyst in argon atmosphere, in toluene medium, at temperature 140-160°C for 2-4 h. The yield of the end product is 68-89%. Proposed compounds can be used as chelate compounds, sorbents, biologically active compounds and in the development of material with required electronic, magnetic and optical properties.

EFFECT: improved method of synthesis, valuable properties of compounds.

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel triazole derivative of the general formula (I): wherein R1 represents phenyl group optionally substituted with one or two groups chosen from (C1-C6)-alkyl group, (C1-C6)-halogenalkyl group, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkoxy-group, halogen atom, nitro-group or cyano-group, styrenyl group, (C1-C6)-alkoxystyrenyl-group or pyridyl group; R2 represents methyl or amino-group; A and B are carbon atoms; C and D represent independently carbon or nitrogen atom, and its nontoxic salt and pharmaceutical composition based on thereof. Also, invention relates to methods for synthesis of novel compounds, novel intermediate substances of the formula: wherein R2, A, B, C and D have above given values; n means a whole number from 0 to 2, and to a method for their synthesis. Compounds of the formula (I) possess anti-inflammatory activity and can be used potentially in treatment of fever, pain and inflammation.

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

9 cl, 2 tbl, 50 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

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

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

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

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 1-91-methyl-2-(3,4-fullero[60]-pyrrolidinyl))-1H-1,2,4-triazole of the general formula (1): Method involves interaction of fullerene[60] with N-[(1,2,4-triazol-1-yl)methyl]-N,N-dimethylamine of the general formula: (R-CH2-N-(CH3)2 wherein R means taken in the mole ratio C60 : R-CH2-N-(CH3)2 = 0.01:(0.01-0.011) in the presence of Cp2TiCl2 as a catalyst taken in the amount 15-25 mole% relatively to fullerene[60], in argon atmosphere, in toluene medium as a solvent at temperature 140-160°C for 2-4 h. The end substance is prepared with the yield 78-86%. Compound of the formula (1) can be used as chelating agent, sorbent, biologically active compound and in the development of novel materials with required electronic, magnetic and optical properties.

EFFECT: improved method of synthesis.

1 tbl, 1 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: herbicides.

SUBSTANCE: invention relates to application of 2-diethylamino-6-methoxy-4-[(4'-ethoxycarnonyl-5'-methyl-1',2',3'-triazole)-1'yl]1,3,5,-triazine of formula as antidote against phytotoxic action of 2,4-dichlorophenoxyacetic acid herbicide onto germinated sunflower seeds.

EFFECT: more effective sunflower germ root length and hypocotyl elongation on background of phytotoxic 2,4-D herbicide action.

2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of N-heterocyclic compounds of the formula: , wherein n and m mean independently a whole number from 1 to 4; A means -C(O)OR1 or -C(O)N(R1)R2; W means -CH; R1 means hydrogen atom or (C1-C8)-alkyl; R means hydrogen atom, (C1-C8)-alkyl, heterocyclyl-(C1-C4)-alkyl chosen from the group comprising benzodioxolyl-, benzodioxanyl- or dihydrobenzofuranylalkyl or phenyl-(C1-C4)-alkyl substituted possibly with alkoxy-group; R4 means cyano-group or heterocyclyl chosen from the group comprising pyridinyl, morpholinyl, benzodioxolyl or benzodioxanyl-radical if m = 1; if m means from 2 to 4 then R4 can mean additionally hydroxy-group, -NR1R2 wherein R1 and R2 mean independently hydrogen atom, (C1-C8)-alkyl or benzyl-radical, -N(R1)-C(O)-R1, -N(R1)-C(O)-OR1, -N(R1)-S(O)t-R1 wherein R1 means hydrogen atom or (C1-C8)-alkyl, -N(R1)-C(O)-N(R1)2 wherein R1 means hydrogen atom; R5 means (C1-C8)-alkyl; t = 2, and their stereoisomers and pharmaceutically acceptable salts, pharmaceutical composition based on thereof and a method for treatment of diseases, in particular, rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and composition.

12 cl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

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

11 cl, 2 tbl

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: method involves carrying out a seasonal single treatment of plant leaves with asymmetrical derivative of 4,6-bis-(aryloxy)pyrimidine of the formula: wherein X means chlorine atom (Cl), nitro- or cyano-group. Invention provides enhancing the long-term time of plants protection.

EFFECT: enhanced effectiveness and valuable properties of compounds.

6 cl, 6 tbl

The invention relates to new derivatives of di - or triftormetilfullerenov, the General formula I:

where, when R1represents a hydrogen atom or alkyl group with 1-5 carbon atoms, R2represents a hydrogen atom, and when R1is alkoxyalkyl group with 2-6 carbon atoms, R2represents a hydrogen atom or a fluorine atom, or their salts, which are effective for removing a wide variety of weeds, including difficult to suppress weeds that appear in the rice fields, and which are safe for mammals

The invention relates to new substituted aminomethanesulfonic General formula (I) possessing a highly effective herbicide action, as well as the way they are received, herbicide tool based on these intermediate compounds of General formula (II)

The invention relates to an improved method for producing unsymmetrical 4,6-bis(aryloxy)pyrimidine of formula I, which are used in agriculture as pesticides, and to a new intermediate compound of formula II to obtain

The invention relates to a new method of production (its variants) aminophenylalanine formula I, having the properties of plant growth regulators or herbicides, as well as intermediate products for their production

The invention relates to new sulfonamidnuyu derivatives or their pharmaceutically acceptable salts, which have the properties of inhibitor action of endothelin receptors and can find application in the treatment of diseases associated with disorders in the circulatory system, such as hypertension, ischemia, angina, spasms of the blood vessels as well as to pharmaceutical drugs based on them

The invention relates to new derivatives of arylethanolamine formula I or its pharmaceutically acceptable salts, which have a high affinity for endothelin and can find application in medicine

The invention relates to novel acylated to aminophenylacetylene General formula I which possess herbicide action and selectivity of action in comparison with the previously known compounds of this series

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

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

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