The method of obtaining derivatives of 2-aminothiazoline

 

(57) Abstract:

The invention relates to a method for producing derivatives of 2-aminothiazoline formula I, in which R1represents C1-5alkyl straight or branched chain, R2is1-3alkyl, by reacting the compounds of formula II in which R3represents phenyl which may be optionally mono-pentamidine independently chlorine, methoxy, ethoxy, phenoxy or nitro, with the compound of the formula III in which Y represents a leaving group, in a solvent and in the presence of a base. The compound of formula II in which R1represents C1-5alkyl straight or branched chain, R2represents C1-3alkyl, R3represents phenyl which may be optionally mono-to Penta-substituted independently chlorine, methoxy, ethoxy, phenoxy or nitro, and the compound of formula III in which Y represents chlorine or bromine. The technical result is an improvement of the method of obtaining 2-aminothiazoline. 3 c. and 7 C.p. f-crystals, 1 PL.

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The present invention relates to a method for deriving 2-aminothiazoline, represented by the following formula (I):
3-6cycloalkyl, and R2is1-3alkyl or C1-3halogenated.

The compounds of formula (I) are used as microbicides in the treatment of plant diseases caused Pythiaceae or peronosporaceae, genus peronospora. The compounds of formula (I) have already been described in Korean laid out the application 94-19960 and corresponding foreign applications, for example, patent application U.S. 08/287917, patent application Japan 192529 and patent application EP 94112652.6, which were filed by the applicant of this application.

Furthermore, the method of obtaining derivatives of 2-aminothiazoline, including the compounds of formula (I) using 2-aminothiazoline acid as intermediate compounds described in laid Korean application 97-24120. However, the disadvantage of this method is that it is uneconomical in industrial production due to mnogostadiinost obtain the intermediate and low output.

Accordingly, the applicants have conducted studies on the improvement of the previously known method by the above-mentioned problems, and as a result came to the present invention.

The present invention relates to a method for deriving 2-aminothiazole is expressed by the following formula (II):

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in which R1and R2have the meanings defined above, and R3represents phenyl which may be optionally mono - pentamidine independently chlorine, methoxy, ethoxy, phenoxy or nitro,

subjected to reaction with a compound of thiophenated, represented by the following formula (III):

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in which Y represents a leaving group such as chloride, bromide, etc.

The compound of formula (I) can be obtained by reaction of compounds of formula (II) with the compound of the formula (III) in a solvent and in the presence of a base, as described by the reaction scheme I (see the end of the description).

Examples of the base used in the above reaction include organic base, such as triethylamine, tributylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, etc. and an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, etc., an Organic base is preferred, and more preferred is alkylamine, such as triethylamine, tributylamine, diisopropylethylamine, etc., the Base can be used in an amount of from 1 € to be carried out at a temperature between 20oWith the 120oC, preferably between 40oWith 80oWith, and the required reaction time is from about 8 to 12 hours.

The solvent includes an alcohol, such as methanol, ethanol, isopropyl alcohol and so on; aromatic hydrocarbons such as benzene, toluene, xylene and so on ; a simple ether, such as diethyl ether, dioxane, 1,2-dimethoxyethane, tetrahydrofuran and so forth; ketone such as acetone, methyl ethyl ketone, cyclohexanone, etc.,; a nitrile such as acetonitrile, propionitrile and so on; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and so on; esters such as methyl acetate, the ethyl acetate and so on; and a polar solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and so on; and the alcohol is preferred.

The compound of formula (II) used as starting material in reaction scheme I, is new and can be obtained in accordance with reaction scheme II (see below).

In other words, the compound of formula (II) can be obtained according to the method, characterized in that:

in stage 1 the amide compound represented by the following formula (IV):

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in which R2and R3have the meanings given above, lorengo connection represented by the following formula (V):

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in which R2and R3have the meanings defined above;

in stage 2 received imidocloprid compound of formula (V) is subjected to reaction with thiocyanate compound represented by the following formula (VII):

MSCN (VII),

in which M represents an alkaline metal such as sodium, potassium, etc. or NH4,

which chloride group is replaced isothiocyanates group with obtaining amitorization compounds represented by formula (VI):

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where R2and R3defined as described above;

at stage 3 received iminoimidazolidine compound of formula (VI) is subjected to reaction with primary aminoven compound represented by the following formula (VIII):

R1-NH2(VIII)

where R1determined, as described above, in the presence of a base.

In stage 1 to obtain imidocloprid the compounds of formula (V) as the halogenation agent can be used thionyl chloride (Sl2), phosgene (COCl2), phosphorus oxychloride (RES3), etc., Halogenation agent is suitably used in an amount of from 1 to 4 equivalents. This reaction is carried out at teeth usually from 2 to 5 hours. As a base may be used an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, N,N-dimethylaniline, tributylamine, etc. are Preferred weak base, such as pyridine. The base is suitably used in an amount of from 1 to 4 equivalents.

The solvent may be used aromatic hydrocarbons such as benzene, toluene, xylene and so on; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and so on; a simple ether, such as diethyl ether, dioxane, 1,2-dimethoxyethane, tetrahydrofuran, and so forth ; ketone such as acetone, methyl ethyl ketone, cyclohexanone, etc.,; a nitrile such as acetonitrile, propionitrile and so forth; ester such as methyl acetate, ethyl acetate and so on; or a polar solvent, such as N,N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and so on; and, preferably, halogenated hydrocarbons such as dichloroethane, chloroform, etc., in Addition, N,N-dimethylformamide can be used as a catalyst.

In stage 2 iminoimidazolidine compound of formula (VI) are obtained by reaction imidocloprid the compounds of formula (V) obtained in stage 1,the number from 1 to 2 equivalents. The reaction temperature can be between -20oWith the 50oC, preferably between 0oAnd 20oC, and the reaction time preferably ranges typically from 2 to 5 hours.

At stage 3 iminodisuccinate compound of formula (II) is obtained from amitorization the compounds of formula (VI). At this stage, the carbon atom of isothiocyanate attacked aminoven compound of formula (VIII) in the presence of a base, allowing it turns out tiomochevinoi compound of formula (II). Amine compound of the formula (VIII) may be used in amounts of from 1 to 4 equivalents, preferably 2 to 3 equivalents. This reaction can be carried out at temperatures between -20oWith 80oC, preferably between 0oC and 30oC. the reaction Time is usually from 2 to 4 hours.

The above methods of the present invention will be explained in more detail by the following examples. As typical examples of the compounds of the formula (II) according to the present invention can be mentioned the compounds described in the table (see the end of the description).

The compound of formula (III) used as starting substances in the reaction scheme (I), is also new and can be floor is(III) can be obtained according to the method, characterized in that in stage 1 of the aldehyde compound represented by the following formula (IX):

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turn in aminonitriles the compound represented by the following formula (X):

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by known synthesis Striker;

in stage 2 received aminonitriles compound of formula (X) enter into reaction with the compound represented by the following formula (XI):

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where Y is defined as described above, in the presence of a base.

In stage 1 of the above-described reaction of the aldehyde compound of the formula (IX) can be easily transformed into aminonitriles compound of formula (X) by known synthesis Striker, as indicated above.

In stage 2 thiophenated compound of formula (III) can be obtained by reaction aminonitriles the compounds of formula (X) with 1-3 equivalents, preferably about 1-1 .5 equivalents of chloroacetanilide or bromoacetamide formula (XI) in the presence of a base. This reaction can be carried out at temperatures between -20oWith 80oC, preferably between 0oAnd 20oC. the reaction Time is suitably from 30 minutes to 2 hours.

As the base can be used an organic base, such as occhialino pyridine or 4-dimethylaminopyridine. The base may preferably be used in amounts of from 1 to 3 equivalents.

The solvent can be used halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and so on; aromatic hydrocarbons such as benzene, toluene, xylene and so on; a simple ether, such as diethyl ether, dioxane, 1,2-dimethoxyethane, tetrahydrofuran and so forth; ketone such as acetone, methyl ethyl ketone, cyclohexanone, etc.,; a nitrile such as acetonitrile, propionitrile and so forth; ester such as methyl acetate, ethyl acetate and so on; or a polar solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and so on; and, preferably, halogenated hydrocarbons or aromatic hydrocarbons.

The present invention is explained in more detail using the following preparative examples and examples. However, it should be clear that the present invention is in no way limited to these examples.

Preparative example 1: Synthesis of N-phenylpropionamide

In the reaction vessel is placed aniline (279,4 g, 3.0 mol) and dichloromethane (2400 g), the reaction vessel is cooled to 0oWith and slowly add it dropwise sodium hydroxide (132,0 g, 3,3 oWith it dropwise within 2 hours add propionate (291,5 g, 3.2 mol). The mixture is then stirred at room temperature (20o(C) within 2 hours and the reaction ends. After completion of the reaction, the layers are separated and the dichloromethane is removed by distillation under reduced pressure, obtaining a brown solid. The solid is recrystallized from toluene, getting mentioned in the title compound (434,7 g, 2.9 mol) yield 97%.

1H NMR (Dl3): of 7.75 (1H, s, W), 7,52 (2H,d), 7,29 (2H, d), was 7.08 (1H, t), is 2.37 (2H, square), to 1.22 (3H, t).

Example 1: Synthesis of N-ethyl-N'-(1-phenylaminopropyl)urea

N-phenylpropionamide (149,2 g, 1.0 mol) and pyridine (261,0 g, 3.3 mol) is dissolved in dichloromethane (300 g) and the mixture cooled to 0oC. To it is added dropwise over two hours added phosphorus oxychloride (168,7 g, 1.1 mol) and the mixture is then stirred at room temperature (20oC) for 2 hours to obtain N-phenylpropionaldehyde.

Subsequently, the reagent for 2 hours slowly added dropwise into the reaction vessel containing a mixture of potassium thiocyanate (145,8 g, 1.5 mol) and potassium carbonate (318,0 g, 3.0 mol) in acetone (1000 ml) at a temperature of 10oWith or below and the mixture is then stirred for 1 by ethylamine (128,8 g, 2.0 mol), maintaining the temperature of 10oC or lower, and then the mixture is stirred for 1 hour.

After completion of the reaction the solvent is removed by distillation under reduced pressure. The product is extracted with toluene and washed with sodium hydroxide solution. Then the toluene is removed by distillation under reduced pressure and the residue is recrystallized from isopropyl alcohol, getting mentioned in the title compound (157,2 g, 0.7 mol) yield 67%.

1H NMR (Dl3): 11,84 (1H, s, W), 8,18 (1H, s, W), to 7.32 (2H, m), 7,12 (1H, t), 6,79 (2H, d), of 3.69 (2H, m), of 2.23 (2H, square), of 1.26 (3H, t) and 1.15 (3H, t).

Example 2: Synthesis of N-(1-(2,4-dichlorophenyl)aminopropyl)) -N' -ethylthiophene

N-(2,4-dichlorobenzene)propionamide (21.8 g, 0.1 mol) and pyridine (27.7 g, 0.35 mol) is dissolved in dichloromethane (30 g) and the mixture cooled to 0oC. To it is added dropwise over two hours added phosphorus oxychloride (16,9 g, 0.11 mol) and the mixture is then stirred at room temperature (20oC) for 2 hours to obtain N-(2,4-dichlorobenzene) propionamidoxime.

After this reagent for 2 hours slowly added dropwise into the reaction vessel containing a mixture of potassium thiocyanate (14.6 g, 0.15 mol) and potassium carbonate (31.8 g, 0.3 mol) in acetone (100 ml) 6-dichlorobenzene)propionamidoxime. In the reaction vessel for 2 hours added dropwise ethylamine (12.9 g, 0.2 mol), maintaining the temperature of 10oC or lower, and then the mixture is stirred for 1 hour.

After completion of the reaction by the same procedure as in example 1, get mentioned in the title compound (21,9 g, 72 mmol) with a yield of 72%.

1H NMR (Dl3): of 11.69 (1H, s, W), 8,65 (1H, s, W), the 7.43 (1H, d), 7,21 (1H, m), is 6.78 (1H, d), 3,70 (2H, m), of 2.23 (2H, square), of 1.27 (3H, t) to 1.14 (3H, t).

Example 3: Synthesis of N-isopropyl-N'- (1-phenylaminopropyl) thiourea

N-phenylpropionamide (7,46 g, 0.05 mol) and pyridine (13.8 g, 0.18 mol) is dissolved in dichloromethane (300 g) and the mixture cooled to 0oC. To it is added dropwise over two hours added phosphorus oxychloride (8,43 g, 0.05 mol) and the mixture is then stirred at room temperature (20oC) for 2 hours to obtain N-phenylpropionaldehyde.

Subsequently, the reagent for 2 hours slowly added dropwise into the reaction vessel containing a mixture of potassium thiocyanate (7,3 g, 0.08 mol) and potassium carbonate (15.9 g, 0.15 mol) in acetone (50 ml) at a temperature of 10oWith or below and the mixture is then stirred for 1 hour to obtain isothiocyanate N-phenylpropionaldehyde. In the reaction vessel already, and then the mixture is stirred for 1 hour.

After completion of the reaction by the same procedure as in example 1, get mentioned in the title compound (8.1 g, 0.03 mol) yield 65%.

1H NMR (Dl3): RS 11.80 (1H, s, W), a 7.92 (1H, s, W), to 7.35 (2H, m), 7,13 (1H, t), 6,79 (2H, d), 4,50 (1H, m), of 2.25 (2H, square), of 1.28 (3H, s) to 1.22 (3H, s) of 1.17 (3H, t).

Example 4: Synthesis of 2-chloro-N-(-cyano-2-Tennille) ndimethylacetamide

Hydrochloride aminothiophene-2-yl-acetonitrile (17.5 g, 0.1 mol) dissolved in dichloromethane (100 ml) and then add to it pyridine (16.6 g, 0.21 mol). The mixture is cooled to 10oWith and then for 1 hour added to it dropwise chlorocatechol (12.4 g, 0.11 mol).

After completion of the reaction the mixture is washed three times with water (60 ml each wash), the solvent is removed by distillation under reduced pressure and the residue is recrystallized from toluene, getting mentioned in the title compound (19,8 g, 0.09 mol) yield 92%.

1H NMR (Dl3): 7,42 (1H, d), 7,32 (1H, d), 7.23 percent (1H, s, W), 7,05 (1H, t), 6,28 (1H, d), is 4.15 (2H, s).

Example 5: Synthesis of 2-ROM-N-(-cyano-2-Tennille)ndimethylacetamide

Hydrochloride aminothiophene-2-yl-acetonitrile (8.8 g, 0.05 mol) is dissolved in dichloromethane (50 ml) and then add to it pyridine (8.7 g, 0.11 mol). The mixture is tx2">

After completion of the reaction by the same procedure as in example 4, get mentioned in the title compound (11.4 g, 0.04 mol) yield 88%.

1H NMR (Dl3): 7,41 (1H, m), 7,32 (1H, m), 7,11 (1H, d, W), 7,05 (1H, m), and 6.25 (1H, d), of 3.94 (2H, s).

Example 6: Synthesis of N-cyano-2-Tennille)-4-ethyl-2- (ethylamino) -5-thiazolecarboxamide

Method 1

N-ethyl-N'-(1-phenylaminopropyl) thiourea (23,5 g, 0.1 mol) and 2-chloro-N-(-cyano-2-Tennille)ndimethylacetamide (21,4 g, 0.1 mol) is dissolved in methanol (200 ml). Then the mixture is injected triethylamine (15.2 g, 0.15 mol) and the mixture refluxed for 8 hours.

After completion of the reaction the mixture is cooled and filtered. The residue was washed with cold methanol and dried, obtaining specified in the header connection (24,0 g, 0.08 mol) with a yield of 75%.

Method 2

N-(1-(2,6-dichlorophenyl) aminopropyl)-N'- ethylthiophene (31 g, 0.1 mol) and 2-xnop-N-(-cyano-2-Tennille)ndimethylacetamide (21,4 g, 0.1 mol) is dissolved in methanol (200 ml). Then the mixture is injected triethylamine (15.2 g, 0.15 mol) and the mixture refluxed for 8 hours.

After completion of the reaction the mixture is cooled using cold methanol and dried to obtain specified in the connection header (24,0 g, 0.08 mol) with a yield of 75%.

,26 (6N, m).

Example 7: Synthesis of N-cyano-2-Tennille)-2-(ethylamino)-4-methyl-5-thiazolecarboxamide

N-ethyl-N'-(1-phenyliminomethyl) thiourea (22.1 g, 0.1 mol) and 2-chloro-N-(-cyano-2-Tennille) ndimethylacetamide (21,4 g, 0.1 mol) is dissolved in ethanol (200 ml). Then the mixture is injected diisopropylethylamine (15.5 g, 0.12 mol) and the mixture is stirred at a temperature of 60oC for 10 hours.

After completion of the reaction the solvent is removed by distillation under reduced pressure, obtaining a brown solid. The solid is recrystallized from a mixture of toluene and water (volume ratio of 10/1) to obtain the specified title compound (22.1 g, 0.07 mol) yield 72%.

1H NMR (Dl3): of 7.36 (1H, d), 7,30 (1H, d),? 7.04 baby mortality (1H, t), 6,10 (1H, d), of 5.99 (1H, s, W), of 3.28 (2H, square), 2,53 (2H, s) of 1.30 (3H, t).

Example 8: Synthesis of N-cyano-2-Tennille)-4-ethyl-2-(isopropylamino) -5-thiazolecarboxamide

N-isopropyl-N'-(1-phenylaminopropyl)thiourea (2.5 g, the 0.01 mol) and 2-bromo-N-(-cyano-2-Tennille)ndimethylacetamide (2.6 g, 0.01 mol) is dissolved in methanol (20 ml). Then the mixture is injected triethylamine (1.5 g, 0.02 mol) and the mixture is stirred at a temperature of 60oWith over 7 hours.

After completion of the reaction the solvent is removed by distillation under reduced pressure, getting brown, the second ratio 1/1), getting listed in the title compound (2.0 g, 0.01 mol) with an output of 60%.

1H NMR (Dl3): 7,38 (1H, d), 7,30 (1H, d), 7,01 (1H, t), 6,44 (1H, d), 6,00 (1H, d), 5,49 (1H, s, W), 3,61 (1H, m), 2.91 in (2N, square), 1.27mm (N, m).

Example 9: Synthesis of N-ethyl-N'-(1-(4-phenoxyphenyl)aminopropyl)-thiourea

N-(4-phenoxybenzoyl)propionamide (120,6 g, 0.5 mol) and pyridine (to 130.6 g of 1.65 mol) is dissolved in dichloromethane (200 g) and the mixture cooled to 0oC. To the mixture dropwise over two hours added phosphorus oxychloride (84,3 g, 0.55 mol), and the mixture is then stirred at room temperature (20oC) for 2 hours to obtain N-(4-phenoxybenzoyl) propionamidoxime.

Subsequently, the reagent is slowly added dropwise into the reaction vessel containing a mixture of potassium thiocyanate (72,9 g, 0.75 mol) and potassium carbonate (159,0 g, 1.5 mol) in acetone (500 ml) at a temperature of 10oC or lower within 2 hours and then the mixture is stirred for 1 hour to obtain isothiocyanate N-(4-phenoxybenzoyl)propionamide. In the reaction vessel are added dropwise ethylamine (64.4 g, 1.0 mol), maintaining the temperature of 10oWith or less within 2 hours, and then the mixture is stirred for 1 hour.

After completion of the reaction the solvent is removed GTG the toluene is removed by distillation under reduced pressure and the residue is recrystallized from isopropyl alcohol to obtain specified in the connection header (of 98.2 g, 0.3 mol) yield 60%.

1H NMR (Dl3): of $ 11.97 (1H, s), of 8.90 (1H, s), 7,33 (3H, m), 7,01 (4H, m), 6.75 in (2H, m), 3,68 (2H, square), 1,25 (3H, T.), of 1.16 (3H, t).

Example 10: Synthesis of N-ethyl-N'-(1-(4-methoxyphenyl)aminopropyl)-thiourea

N-(4-methoxybenzoyl)propionamide (89,6 g, 0.5 mol) and pyridine (to 130.6 g of 1.65 mol) is dissolved in dichloromethane (200 g) and the mixture cooled to 0oC. To the mixture dropwise over two hours added phosphorus oxychloride (84,3 g, 0.55 mol), and the mixture is then stirred at room temperature (20oC) for 2 hours to obtain N-(4-methoxybenzoyl) propionamidoxime.

Subsequently, the reagent is slowly added dropwise into the reaction vessel containing a mixture of potassium thiocyanate (72,9 g, 0.75 mol) and potassium carbonate (159,0 g, 1.5 mol) in acetone (500 ml) at a temperature of 10oWith or less within 2 hours, and the mixture is stirred for 1 hour to obtain N-(4-methoxybenzoyl)propionylthiocholine. In the reaction vessel are added dropwise ethylamine (64.4 g, 1.0 mol) maintaining the temperature of 10oWith or less within 2 hours, and then the mixture is stirred for 1 hour.

After completion of the reaction the solvent is removed by distillation under reduced pressure. The product is extracted with toluene and p is crystallizability from isopropyl alcohol to obtain specified in the connection header (84,9 g, 0.32 mol) yield 64%.

1H NMR (Dl3): 11,90 (1H, s), to 8.12 (1H, s), 6.87 in (2H, d), of 3.80 (3H, s), of 3.69 (2H, square), 2,24 (2H, square), of 1.26 (3H, etc), to 1.14 (3H, t).

Example 11: Synthesis of N-ethyl-N'-(1- (4-nitrophenyl) aminopropyl) -thiourea

N-(4-nitrobenzoyl)propionamide (to 19.4 g, 0.1 mol) and pyridine (26,1 g, 0.33 mol) is dissolved in dichloromethane (30 g) and the mixture cooled to 0oC. To the mixture dropwise over two hours added phosphorus oxychloride (16,9 g, 0.11 mol), and the mixture is then stirred at room temperature (20oC) for 2 hours to obtain N-(4-nitrobenzene)propionamidoxime.

Subsequently, the reagent is slowly added dropwise into the reaction vessel containing a mixture of potassium thiocyanate (14.6 g, 0.15 mol) and potassium carbonate (31.8 g, 0.3 mol) in acetone (100 ml) at a temperature of 10oWith or less within 2 hours, and the mixture is stirred for 1 hour to obtain N-(4-nitrobenzene)propionylthiocholine. In the reaction vessel are added dropwise ethylamine (12.9 g, 0.2 mol), maintaining the temperature of 10oWith or less within 2 hours, and then the mixture is stirred for 1 hour.

After completion of the reaction the solvent is removed by distillation under reduced pressure. The product is extracted with toluene and washed Tlisova from isopropyl alcohol to obtain specified in the connection header (17,4 g, 0,062 mol) yield 62%.

1H NMR (Dl3): 11,20 (1H, s), 8,23 (2H, d), 7,88 (1H, s), 6,92 (2H, d), 3,71 (2H, square), 2,22 (2H, square), of 1.28 (3H, T.), of 1.17 (3H, t).

Example 12: Synthesis of N-cyano-2-ethyl)-4-ethyl-2-(ethylamino)-5-thiazolecarboxamide

Method (A)

Obtaining the target compound using source material from phenoxy group

N-ethyl-N'-(1-(4-phenoxyphenyl)aminopropyl)thiourea (32.7 g, 0.1 mol) and 2-chloro-N-(-cyano-2-Tennille)ndimethylacetamide (21,4 g, 0.1 mol) is dissolved in methanol (200 ml). Then the mixture is injected triethylamine (15.2 g, 0.15 mol) and the mixture heated under reflux for 8 hours. After completion of the reaction the mixture is cooled and filtered. The residue was washed with cold methanol and dried to obtain specified in the connection header (22,5 g, 0.07 mol) with access to 70.2%.

Method)

Obtaining the target compound using the source material with a methoxy group

N-ethyl-N'-(1-(4-methoxyphenyl)aminopropyl)thiourea (26.5 g, 0.1 mol) and 2-chloro-N-(-cyano-2-Tennille)ndimethylacetamide (21,4 g, 0.1 mol) is dissolved in methanol (200 ml). Then the mixture is injected triethylamine (15.2 g, 0.15 mol) and the mixture heated under reflux for 8 hours. After completion of the reaction the mixture is cooled and filtered. The residue is washed kholodnyakov)

Obtaining the target compound using source material from the nitro group

N-ethyl-N-(1-(4-nitrophenyl)aminopropyl)thiourea (28,0 g, 0.1 mol) and 2-chloro-N-(-cyano-2-Tennille)ndimethylacetamide (21,4 g, 0.1 mol) is dissolved in methanol (200 ml). Then the mixture is injected triethylamine (15.2 g, 0.15 mol) and the mixture heated under reflux for 8 hours. After completion of the reaction the mixture is cooled and filtered. The residue was washed with cold methanol and dried to obtain specified in the connection header (21,5 g, 0.067 mol) with the release of 67.1%. These NMR target connection

1H NMR (Dl3): 7,38 (1H, d), 7,33 (1H, d),? 7.04 baby mortality (1H, T.), to 6.43 (1H, d ), 5,94 (1H, d W), 5,59 (1H, s, W), 3,26 (2H, square), with 2.93 (2H, square ), 1,26 (6N, m).

As described above, derivatives of 2-aminothiazoline formula (I) can be obtained with high yield when using intermediate compounds of formulas (II) and (III) according to the method of the present invention. From the industrial point of view this method is more economical than known, due to the high outputs.

1. The method of obtaining derivatives of 2-aminothiazoline, represented by the following formula I:

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in which R1represents C1-5alkyl straight or branched chain;

Rth II:

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in which R1and R2have the meanings defined above, and R3represents phenyl which may be optionally mono-to Penta-substituted independently chlorine, methoxy, ethoxy, phenoxy or nitro, is subjected to reaction with a compound represented by the following formula III:

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in which Y represents a leaving group, in a solvent and in the presence of a base.

2. The method according to p. 1, in which Y represents chlorine or bromine.

3. The method according to p. 1, in which the solvent is an alcohol selected from the group consisting of methanol, ethanol and isopropyl alcohol, aromatic hydrocarbon selected from the group consisting of benzene, toluene and xylene, a simple ester selected from the group consisting of diethyl ether, dioxane, 1,2-dimethoxyethane and tetrahydrofuran, a ketone selected from the group consisting of acetone, methyl ethyl ketone and cyclohexanone, nitrile selected from the group consisting of acetonitrile and propionitrile, halogenated hydrocarbon selected from the group consisting of dichloromethane, 1,2-dichloro-ethane and chloroform, an ester selected from the group consisting of methyl acetate and ethyl acetate, or a polar solvent selected from the group consisting of what ielem is alcohol.

5. The method according to p. 1, in which the base is an organic base selected from the group consisting of triethylamine, tributylamine, diisopropylethylamine, N, N-dimethylaniline, pyridine and 4-dimethylaminopyridine or inorganic base selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride and potassium hydride.

6. The method according to p. 5, in which the base is an organic base.

7. The method according to p. 1, in which the reaction is carried out at temperatures between 20 and 120oWith over 8 to 12 hours

8. The compound represented by the following formula II:

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in which R represents a C1-5alkyl straight or branched chain;

R2represents C1-3alkyl;

R3represents phenyl which may be optionally mono-to Penta-substituted independently chlorine, methoxy, ethoxy, phenoxy or nitro.

9. Connection on p. 8, in which any one of R1and R2independently represents ethyl.

10. The compound represented by the following formula III:

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in which Y represents chlorine or bromine.

 

Same patents:

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups

The invention relates to compounds of formula (I) R4-A-CH(R3)N(R2)B-R1where a is optionally substituted phenyl group, provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-position relative to each other on the carbon atoms of the ring, and provided that the atom of the ring, in anthopology towards OR4- joined the group (and therefore in the 3-position relative to the-CHR3NR2-linking group) is unsubstituted; In - pyridyl or pyridazinyl; R1located on the ring In the 1,3 - or 1,4-position relative to the-CH(R3)N(R2)-linking group and represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula СОNRaRa1where Rais hydrogen or C1-6alkyl, and Ra1- C1-6alkyl, or R1represents a group of formula CONHSO2Rbwhere Rb- C1-6alkyl, trifluoromethyl, or a 5-membered heteroaryl selected from isooxazolyl and thiadiazolyl, optionally substituted C1-6the alkyl or C1-4alkanolamines; R2- C1-6alkyl; R3is hydrogen; R4- C1-4alkyl, C3-7cycloalkyl,1-3alkyl or their pharmaceutically acceptable salt or in vivo hydrolyzable esters

The invention relates to a method for the preparations of thiazolidinediones of the formula III, where a denotes CH=CH or S, W is O; X Is S, O or NR2where the remainder R2is hydrogen or C1-C6by alkyl; Y is CH or N; R is naphthyl, thienyl or phenyl, which optionally one - or twofold substituted C1-C3the alkyl, CF3C1-C3alkoxygroup, F, Cl or bromine; R1is hydrogen, C1-C6alkyl and n = 1-3, by restoring the compounds of formula IV metal aluminum in proton solvent

The invention relates to a new, more thermodynamically stable crystalline form of the hydrochloride of (R)-(-)-2-{N-[4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl)butyl]aminomethyl}-chroman

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula (I), where R1is non-branched C1-6alkyl group, R2is non-branched C1-6alkyl group, R3is hydrogen, R4represents phenyl, R5R6and R8selected from hydrogen, R7represents a group of formula (Ia) and (IB), where the hydroxy-group may be substituted by acetyl, R16represents-COOH, -CH2-OH, -CH2-O-acetyl-Sooma, R9and R10the same or different and each represents hydrogen or C1-6alkyl group, X represents-O-, or its salt, solvate and physiologically acceptable derivative

The invention relates to a medicinal product on the basis of derivatives of thiazole or thiadiazole of the formula I, where a denotes a linear or branched C1-C18-alkylenes group which may contain at least one group selected from the group consisting of: O, S, NR3, СОNR3, NR3CO, COO, OCO or double or triple bond; In denotes the radical of the formula II, R1denotes H, halogen JV CO2R2, NR2R3, OR SIG3, CF3or C1-C8-alkyl, which is unsubstituted or substituted HE OS1-C8-alkyl or halogen; R2denotes H, C1-C8-alkyl, which is unsubstituted or substituted HE OS1-C8-alkyl or halogen, or phenyl-C1-C8-alkyl; R3has the meanings given for R2or indicate СОR2or CO2R2; X represents N or CR4where R4denotes H, C1-C8-alkyl, which is not substituted or is substituted by IT, OS1-C8-alkyl or halogen, or denotes phenyl which is not substituted or substituted with halogen, CF3C1-C8-alkyl or C1-C8-alkoxy; Ar denotes phenyl, pyridyl, pyrimidyl or triazinyl,

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 a method for Cefotaxime formula I by reacting acetone compounds of the formula II with the compound of the formula III and subsequent, if necessary, converting the compounds of formula I in the presence of a source of sodium ions in a mixture of acetone and water in the sodium salt of Cefotaxime in the form of rounded agglomerates with a bulk density of 0.2-0.6 g/ml or in the form of needle-shaped crystals

The invention relates to new derivatives of tamilcanadian with the General formula (I) wherein R' represents 2-thienyl or 3-thienyl radical, R represents ceanorhaditis or a radical of the formula-C(O) - and R2 is optional saturated or unsaturated cyclic hydrocarbon radical or aryl radical

The invention relates to the field of pharmaceutical chemistry and synthetic organic chemistry and represents the asymmetric synthesis of the key intermediate compound in obtaining DULOXETINE - antidepressant tools

The invention relates to substituted guanidines thiophenemethylamine acid of the formula I

< / BR>
where mean:

at least one of the substituents R(1), R(2) and R(3)

- Op-(CH2)s-CqF2q+1, R(40)CO - or R(31)SOk-;

p is zero or 1;

s is zero, 1, 2, 3 or 4;

q 1,2, 3,4, 5, 6, 7 or 8;

k is zero, 1 or 2;

R(40) alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms,

cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF, methyl or methoxy;

R(31) alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl or methoxy;

or

R(31) NR(41)R(42);

R(41)and R(42)

independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms,

perfluoroalkyl with 1, 2, 3 or 4 C-atoms,

or

R(41)and R(42)

together 4 or 5 methylene groups, of which CH2-group may be replaced by oxygen, S, NH, N-CH3or N-benzyl;

and sootwetstwii-OgaWITHraH2raR(10);

PA zero or 1;

mA zero, 1, 2, 3, 4, 5, 6, 7 or 8;

ga zero or 1;

ha zero, 1, 2, 3 or 4;

R(10) cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl, where the phenyl is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl and methoxy;

R(4) and R(5)

independently from each other hydrogen, F, Cl, Br, I, CN, alkyl with 1, 2, 3, 4, 5, 6,

7 or 8 C-atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(14)R(15);

R(14)R(15)

independently from each other H, alkyl with 1, 2, 3 or 4 C-atoms or perfluoroalkyl of 1, 2, 3 or 4 C-atoms

and their pharmaceutically tolerable salts

The invention relates to a piperidine derivative of General formula I

< / BR>
and their pharmaceutically acceptable salts, where R1is hydrogen, C1-C6-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, C6-C10aryl that may be substituted for CH3, halogen, OR5where R5- C1-C6-alkyl, C1-C2-alkyl-heteroaryl containing as heteroatoms of S, N or O; And a is phenyl, substituted carbonyl or amino group; - C6-C10-aryl or C5-C10-heteroaryl containing as heteroatoms of S, N or O

The invention relates to compounds of formula (I), where R1and R2are cycloalkyl group, aryl group, heterocyclic group; R3and R4is a hydrogen atom or alkoxygroup; R5is a hydrogen atom, alkyl; R6the hydroxy - group, alkoxygroup, allylthiourea or amine residue, X and Y are an oxygen atom; Z represents a single bond between the said nitrogen atom and the benzene ring or alkilinity group G is a direct bond, alkyl, alkylen, the dotted line indicates a single or double bond, D is a carbon atom; E - =N-O-group

The invention relates to new derivatives of tamilcanadian with the General formula (I) wherein R' represents 2-thienyl or 3-thienyl radical, R represents ceanorhaditis or a radical of the formula-C(O) - and R2 is optional saturated or unsaturated cyclic hydrocarbon radical or aryl radical

The invention relates to new derivatives of tamilcanadian with the General formula (I) wherein R' represents 2-thienyl or 3-thienyl radical, R represents ceanorhaditis or a radical of the formula-C(O) - and R2 is optional saturated or unsaturated cyclic hydrocarbon radical or aryl radical

The invention relates to novel 2,5-disubstituted tetrahydrofuran or tetrahydrothiophene formula I

< / BR>
where Ar is phenyl, which is optionally substituted by at least one group selected from halo (including, but not limited to, fluorine), lower alkoxy (including methoxy), lower aryloxy (including phenoxy), cyano, or R3;

m = 1;

W is independently - AN(OM)C(O)N(R3R4, -AN(R3)C(O)N(OM)R4, -AN(OM)C(O)R4AC(O)N(OM)R4, -C(O)N(OM)R4or-C(O)NHA;

A - lower alkyl, lower alkenyl or lower quinil, in which one or more carbons optionally may be replaced by O, N or S;

M is hydrogen, a pharmaceutically acceptable cation;

X IS O,S;

Y is O, S, hydrogen, lower alkyl, lower alkenyl, lower quinil, alkaryl;

R1and R2independently is hydrogen, lower alkyl, halo, or-COOH;

R3and R4independently is hydrogen, alkyl, alkenyl, quinil,1-6alkoxy-C1-C10alkyl or C1-6alkylthio-C1-10alkyl,

which possess anti-inflammatory activity through inhibition of 5-lipoxygenase as PAF receptor antagonists and are dual activity, t

The invention relates to a method for tetrahydrothiophene is used as the odorant gases and feedstock for the synthesis of various valuable organic substances
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