The method of obtaining the sulfonylureas and product fitting

 

(57) Abstract:

Describes a new method of obtaining the sulfonylureas and the product of the merger of General formula I where X is oxygen or-SO2NR2; Y is nitrogen or CH; R1-(C1-C6)alkyl, or when X represents oxygen, (C1-C4)alkoxyphenyl; R2-(C1-C6)alkyl; R3, R4-independently from each other (C1-C4)alkyl or (C1-C6)alkoxy; R5is hydrogen or (C1-C4)alkyl and R6is hydrogen, characterized in that the Ia), the compound of formula III, R8-OCN, where R8is hydrogen, or a Quaternary ammonium ion or one equivalent of a one-, two -, or polyvalent metal cations, if necessary in the presence of the compounds of formula II, R1-X-R7where R1and X have the same meanings as in formula I, and R7is hydrogen, or a Quaternary ammonium ion or one equivalent of a one-, two -, or polyvalent metal cations expose with a compound of formula IV SO2Cl2, IB) obtained in stage Ia) adduct after isolation or without isolation is subjected to interaction with the compound of the formula II and IC) that is obtained in stage IB) adduct after isolation or without isolation in the and in the formula I. The technical result - the new, easy way of obtaining, which can be obtained from the effective compounds of formula I. 2 C. p. and 11 C.p. f-crystals, 1 table.

The invention relates to a method for producing substituted in the heterocycle of the sulfonylureas as the basis of herbicides, namely compounds of the formula I

< / BR>
where X is oxygen, -0 - or-SO2-NR2-;

Y is nitrogen or CH,

R1- (C1-C6)alkyl, or when X is oxygen, (C1-C4) alkoxyphenyl,

R2- (C1-C6)alkyl,

R3, R4-independently from each other (C1-C4)alkyl or (C1-C4) alkoxy,

R5is hydrogen or (C1-C4) alkyl and

R6- hydrogen.

Preferred compounds of formula I, where

R1X - N- [(C1-C6) -alkylsulfonyl] - N - [(C1-C3) -alkyl] -amino, or [(C1-C4) alkoxy] -phenoxy,

R3, R4- independent from each other (C1-C2) alkyl or (C1-C2) alkoxy,

R5is hydrogen or methyl and

R6- hydrogen.

Especially preferred compounds of formula I, where R1X - N -[(C1-C3) alkyl-sulfonyl] -N -[((C1-C2) alkyl]am the

Formula I also includes all unspecified possible stereoisomeric options defined by their specific spatial form, such as enantiomers, diastereomers, Z - and E-isomers, which are referred to in paragraph 1 pair of atoms. Such compounds of formula I contain, for example, one or more asymmetric C atoms or also have double bonds, especially not specified in the formula 1. Stereoisomers can be obtained in the usual way from mixtures of the stereoisomers or by stereoselective reactions in combination with the use of stereochemical pure starting materials.

The compounds of formula I can form salts in which the hydrogen-SO2-NH-group may be substituted, in particular, used in agriculture suitable cation. These salts can represent, for example, metal salts, in particular alkali metal salts (for example, Na+or K+as the cation and /or salts of alkaline earth metals or ammonium salts or salts with organic amines. The formation of salts can also occur by attaching a strong acid to the pyrimidine part of the compounds of formula I. Suitable acids for this purpose are strong norgani is known and used as a means of protecting plants from herbicide action. For more information, see EP-A-013258 /USA-And-4601747/, EP-A-0342569 /USA-And-5104443/ and EP-A-4163/USA-And-4191553/. The mentioned publications cited or are several methods of obtaining, by which one can obtain the compounds of formula I. Additionally, in the known methods the authors particularly focus on the application of chlorosulfonylisocyanate, high reactivity which grows into a serious security issue, and inaccessibility associated with high capital costs. Therefore, the known methods cannot be recommended for use in large industrial scale, both from the point of view of security, and environmental reasons.

So they had found a new method of production, which can be obtained unexpectedly effective compounds of formula I by reacting readily available starting materials.

The object of the present invention is a method of obtaining the above mentioned compounds of formula I. the Method is that

I a) compound of formula III

R8- OCN,

where R8is hydrogen, or a Quaternary ammonium ion or one equivalent of a one-, two -, or polyvalent metal cations, if necessary in the presence connect7is hydrogen, or a Quaternary ammonium ion or one equivalent of a one-, two -, or polyvalent metal cations, is subjected to the interaction with the compound of the formula IV

SO2Cl2< / BR>
Ib) obtained in stage I) adduct after isolation or without isolation is subjected to interaction with the compound of the formula II, and

I) that is obtained in stage Ib) adduct after isolation or without isolation is subjected to interaction with the compound of the formula V

< / BR>
where R3, R4, R5X and Y have the same meanings as in formula I.

Preferably, if R1X-N/(C1-3)-alkylsulfonyl-/-N-/(C1-2) alkyl/-amino, particularly N-(methylsulphonyl)-(methyl)-amino, -N-(methylsulphonyl)-N-(ethyl)-amino, N-(ethylsulfonyl)-N-(methyl)-amino or N-(p-propylsulfonyl)-N-(methyl)-amino. Also preferred are compounds where R1X- (C1-3)-alkoxyphenyl, in particular 2-methoxyphenoxy, 2-ethoxyphenoxy, 2-n-propoxyphene or isopropoxyphenoxy.

Preferably also, if R3and R4- independently from each other (C1-2)-alkyl or (C1-2)-alkoxy, in particular methyl or methoxy.

Examples for R7and R8are cations or alkaline SEL is it 1 associated, respectively, two or more radical in the formula, R1- X compounds of formula II, as well as several radicals OCN in compounds of formula III with metal ions. Examples for R7and R8are Quaternary ammonium ions, such as, for example, tetraalkylammonium, trialkylaluminium, dialkyldimethylammonium, alkyltrimethylammonium and tetraamine, and aryl radicals can be, if necessary, accordingly substituted, for example, alkoxy or aryl.

In the above formulas and further containing hydrocarbon radicals are alkyl-, alkoxy-, the hydrocarbon fragment can be pramocaine or branched. Alkyl radicals, also in meanings such as alkoxy, means methyl, ethyl, n - or isopropyl, n-, ISO-, tert - or 2-butyl.

Output obtained in accordance with the invention of the sulfonylureas of the formula I is relatively high, such as 80% or more, and attain purity of more than 94 wt.%, basically not using the cleanup phase.

The reaction is preferably carried out in two or more stages. First of all, when this reacting together compounds of formula II, III and IV. Then, the thus obtained reaction mixture is replaced by the compounds of the formula V. Encountered with the joint supply of reagents CLASS="ptx2">

The reaction temperature in the interaction of components II, with the adduct of compounds III and IV lies preferably in the range from 0 to 200oC, in particular between 8 to 135oC, especially in the range from 20 to 90oC. the temperature of the interaction between III and IV is in the range from 0 to 80oC.

The reaction temperature interaction with aminoheterocycles V should be maintained between -20oC to 120oC, in particular between -5oC to 80oC.

The method according to the invention can be carried out without using solvent. However, it is often advantageous method or its separate stages carried out in the presence of inert data for the reaction conditions of inorganic or organic solvents or mixtures of these solvents. Also is advantageous to change the solvent between the stages of the method.

Examples of the most suitable organic solvents are pratices polar organic solvents, such as aliphatic or aromatic NITRILES, N, N-dialkylacrylamide, diallylsulfide, polyalkyleneglycol esters and N-alkylated cyclic amides, and aliphatic or preferably aromatic, if the need is I this purpose, inorganic solvents are liquid sulfur dioxide and liquid hydrocyanic acid, as well as their mixtures. You can also use mixtures of these organic and inorganic solvents.

Preferred solvents are, for example, acetonitrile, propionitrile, benzonitrile, dimethylformamide, dimethylsulfoxide, sulfonyl, N-organic, etilenglikolevye ether, di - tri - or tetraethyleneglycol ether, in particular dimethyl or diethyl ether, toluene, xylene, chlorobenzene, liquid sulfur dioxide, or mixtures of two or more of the mentioned solvents. The most appropriate interaction II, III and IV hold, for example, in polar pratices organic or inorganic solvent, such as, for example, acetonitrile or liquid sulfur dioxide, and the next stage or next stage done in less polar aprotic organic solvent such as xylene or toluene.

If the compounds of formula II and/or formula III is not fully dissolved in the selected for this purpose, the solvent, the reaction can be accelerated by intensive mixing of the reaction components, for example, using a mixer or ultrasound.

For the reaction between compounds of formulae II, III and IV is first made by the collaboration is outstay one of these pratices polar organic or pratices polar inorganic solvent, moreover, in the course of the reaction is a product of the merger outstanding patterns (adduct 1). Then spend the reaction of interaction of compound (II) obtained at the preliminary stage of the adduct 1, the easiest way in the form of pre-obtained reaction mixture, if necessary under heating, and in the course of interaction again formed product to be joining the outstanding patterns (adduct 2) used for the present invention in the reaction with the compound of the formula V. Interaction with the compound II is carried out, for example, when the reaction temperature from 0 to 200oC, preferably from 8oC to 135oC, in particular from 20oC to 90oC, in the presence of one of these aprotic polar organic or pratices polar inorganic solvent. It is often advantageous to conduct the specified interaction of the compounds II, III and IV instead of the constant temperature take-mode increasing temperature range.

According to research results and data spectroscopic analysis of the resulting intermediate products are not isocyanate formulae R1XSO2-N= C= O, as originally envisaged, and are adducts connect the urea of formula I, in other words, what is the product that you would expect at a reaction between isocyanate of formula R1XSO2NCO with an amine of the formula V.

Therefore, the object of the present invention are also named adducts 1 and 2 obtained by the above variants of interaction of compounds II and IV or the ensuing reaction with compound II in accordance with the method according to the invention.

In another method the connection method connection formulas II, III and IV, are presented together, preferably heated at a low temperature to -10oC or below together and heated to the reaction temperature. In accordance with another modification of the method of the compounds of formulas II and III can be rented together and sulfurylchloride (compound of formula (IV) is added before heating to the reaction temperature or at the temperature of the reaction between the compounds of formula II.

The interaction of the compounds of formulas II, III and IV is preferably carried out in aprotic conditions.

If R7or R8or both radicals represent hydrogen, as a rule, it is advisable for each molar equivalent of hydrogen to take 1 molar equivalent of "auxiliary" OS is for example the carbonates and/or acidic hydrogen carbonates of alkaline earth metals, carbonates of alkali metals and/or their acidic hydrogen carbonate, and the like, or organic bases, such as, for example, trialkylamine.

Advantageously, as a rule, if R7= hydrogen, the compounds of formulas II and III, in which R8- different hydrogen to enter in a molar ratio of II: III is the largest of about 1:2, in particular in a molar ratio of about 1: 2, with at least one molar equivalent of compound III is used as an auxiliary base. If used as the molar ratio of II:III about I:I, if R7- hydrogen, for full interaction advantageously at least the introduction of about one equivalent of other auxiliary base or, if, in addition, R8is hydrogen, at least two equivalents other ancillary basis. As auxiliary bases can be used grounds referred to in the preceding paragraph. If R7and R8each metal cation or fourth cation ammonium compounds II and III can type compounds II and III, and without auxiliary bases in a molar ratio of 1:1.

Sulfurylchloride/connection with formula IV/ preferably equinoo from 1:1 to 1:5. It is also possible to higher surpluses. As a rule, it is advisable to excess added sulfurylchloride be removed by distillation before the addition of compounds of the formula V.

The compounds of formula V can be entered equimolar, in excess or in excess with respect to compounds of formula II. Unreacted part V compounds should be removed from the reaction mixture using conventional methods and re-enter into the reaction process.

The initial compounds of formulas III and IV, are required to obtain the compounds of General formula I by the method according to the invention, generally available commercially or can be readily achieved in accordance with known methods. The compounds of formula II can also be purchased or obtained by similar known methods, for example by interaction of sulfochlorides with amines.

The heterocycles of the formula V can also be obtained in the trade or are readily obtained by the use of appropriate methods, see, for example, patent application US-A-4310470, European patent application EP-A-0027200, patent application US-A-4299960, M. J. Langermana, C. K. Banks, J. Am. Chem. Soc 73, 3011 (1951).

The advantage of the method according to the invention is that the unreacted portion of the compounds is the reaction process.

Insoluble side components, such as, for example, sodium chloride can be separated between the reaction stages.

An additional advantage of the method according to the invention consists, generally, that the desired products of formula I, if necessary, after the addition of water or other polar solvents can fall out of the reaction medium in the form insoluble compounds with a high degree of purity.

In the examples below, the interest amount should be considered weight as any special reservations on this account is not specified.

Examples

1.1-[(N-methylsulphonyl-N-methylamino)-sulfonyl] -3- (4,6-dimethoxy-2-pyrimidyl)-urea

340 g (2,52 mol) of sulfurylchloride served in 1.5 l of acetonitrile and within 20 minutes with vigorous stirring replace 260 g (4.0 mol) of sodium cyanate, introducing the latest in small portions (20oC). Continue stirring for 15 minutes, then added dropwise 222 g (2.0 mol) of N-methylamide methanesulphonate at 25oC, slowly increase the temperature and for 200 minutes with intensive stirring and heated to phlegmy. Then at a pressure of 100 mbar excess sulfurylchloride from the sphere of nitrogen added to 1.5 l of acetonitrile (option can also be used in toluene) and at 0oC make 155 g (1.0 mol) of 2-amino-4,6-dimethoxy-pyrimidine. After 75 minutes, diluted with a mixture of 1.0 l of water, the precipitate was separated and washed. Get 304 g of 1-(N-methylsulphonyl-N-methyl-amino)-sulfonyl-3-(4,6-dimethoxy-2 - pyrimidyl)-urea with a melting point of 176 178oC. the Product corresponds to the sample comparison and after analysis by liquid chromatography under high pressure shows the purity of 96%. Yield 77% of theory.

2.1-(2-Ethoxybenzonitrile)-3-(4,6-dimethoxy-2-pyrimidyl)-urea

26,0 g (0.4 mol) of pulverized sodium cyanate are suspended at room temperature in 200 ml of acetonitrile and within 20 minutes to replace and 28.3 g (0.21 mol) of sulfurylchloride, and the temperature was increased to 44oC. After stirring for 4 hours at 50oC under reduced pressure to produce distillation, cooled to 27oC for 10 minutes, diluted of 27.6 g (0.2 mol) of 2-ethoxyphenol. Stand overnight and at room temperature add 15.5 g (0.1 mol) 2-amino-4,6-dimethoxypyrimidine. Continue to stir for 120 minutes at 50oC and under reduced pressure, the solvent is distilled off, and diluted with 100 ml water, then extracted with dichloromethane. After distillation of the organic solvent OST the leaves 71,6% wt. 1-(2-ethoxybenzonitrile)-3-(4,6-dimethoxy-2-pyrimidyl)-urea. The output is around 89% of theory.

By analogy with examples 1 and 2 were obtained the compounds of formula I (Y=CH), shown in the table below.

1. The method of obtaining the sulfonylureas of the formula I or their salts

< / BR>
where X is oxygen or - SO2NR2;

Y is nitrogen or CH,

R1- (C1-C6)alkyl, or when X is oxygen, (C1-C4) alkoxyphenyl;

R2- (C1-C6)alkyl;

R3, R4- independently from each other (C1-C4)alkyl or (C1-C4)alkoxy;

R5is hydrogen or (C1-C4)alkyl;

R6is hydrogen,

wherein Ia), the compound of formula III

R8- OCN,

where R8is hydrogen, or a Quaternary ammonium ion or one equivalent of a one-, two -, or polyvalent metal cations,

if necessary, in the presence of the compounds of formula II

R1- X - R7,

where R1and X have the same meanings as in formula I;

R7is hydrogen, or a Quaternary ammonium ion or one equivalent of a one-, two -, or polyvalent metal cations,

subjected to interaction with the compound of the formula IV

SO2Cl2,

Ib) that received the Ic) that is obtained in stage Ib) adduct after isolation or without isolation is subjected to interaction with the compound of the formula V

< / BR>
where R3, R4, R5X and Y have the same values in the formula I.

2. The method according to p. 1, characterized in that the compound of the formula I R1-X - N-[(C1-C6)-alkylsulfonyl] -N-[(C1-C3)-alkyl] -amino, or [(C1-C4)alkoxy] -phenoxy; R3, R4- independently from each other (C1-C2)alkyl or (C1-C2)alkoxy; R5is hydrogen or methyl and R6- hydrogen.

3. The method according to p. 1 or 2, characterized in that the compound of the formula I R1-X - N-[(C1-C3)-alkylsulfonyl]-N-[(C1-C2)alkyl]-amino, or [(C1-C3)alkoxy] -phenoxy.

4. The method according to one of paragraphs.1 to 3, characterized in that the compound of the formula I R3and R4denote methyl or methoxy.

5. The method according to one of paragraphs.1 to 4, characterized in that the reaction temperature in the interaction of compounds of formulas III and IV is in the range from 0 to 80oC.

6. The method according to one of paragraphs.1 to 5, characterized in that the reaction temperature in the interaction of the compounds of formula II with the adduct of the compounds of formulas III and IV is in the range from 0 to 200oC.

7. The method according to p. 5 or 6, characterized in that the reaction temperature when vzaimodeystviya fact, that all the way or its separate stages is carried out in the presence of inert under the reaction conditions, inorganic or organic solvents or in mixtures of these solvents.

9. The method according to p. 8, characterized in that the applied solvent from the group of aprotic polar organic solvents, aliphatic and aromatic, may halogeniranih hydrocarbons and mixtures of the mentioned organic solvents.

10. The method according to one of paragraphs.1 to 9, characterized in that compounds of the formulae II, III and IV (stage Ia and Ib) are interacting in an aprotic solvents.

11. The method according to one of paragraphs.1 to 10, wherein R8- metal cation or Quaternary ammonium cation and compounds of formulas I and III apply: a) in the case R7= H, in a molar ratio of no higher than 1:2, or (C) in the case of R7= H, in a molar ratio of approximately 1:1 and in the presence of 1 mol - equivalent of an auxiliary base, different from the compounds of formula III, or (C) in the case of R7= metal cation or Quaternary ammonium cation, in a molar ratio of approximately 1:1 without auxiliary base.

12. The method according to one of paragraphs.1 - 11, characterized in that the compound of formula IV is used in echtem interaction of sodium cyanate with sulfurylchloride at a temperature of from 0 to 80oC in the presence of aprotic polar organic solvent.

 

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< / BR>
where R1, R2= H, lower alkyl, phenyl, substituted SN3, CF3, Cl-group; R3, R4, R5= N, hydroxyalkyl - or amino-group;

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< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

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< / BR>
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15 cl, 3 tbl, 109 ex

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

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

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