Method for preparing substituted alkylamine derivative

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing a substituted alkylamine derivative from the 2-aminothiophenol compound with high industrial yield that can be used as an intermediate compound used in medicine or in agriculture. Invention proposes a method for preparing substituted alkylamine derivative represented by the following general formula (3): wherein X mean halogen atom, alkyl group, alkoxy-group, cyano-group or nitro-group; n means a whole number from 1 to 4; each R1 and R2 means independently hydrogen atom of phenyl-substituted, or unsubstituted alkyl group that can in common form 5- or 6-membered cycle, or its additive acid salt. Method involves addition of 2-aminothiophenol derivative salt represented by the following formula (1): wherein X and n have abovementioned values to acid to provide pH value 6 or less and to convert salt to free 2-aminothiophenol derivative of the general formula (1) followed by addition of 2-aminothiophenol derivative with amino-N-carboxyanhydride to the reaction represented by the following general formula (2): wherein each R1 and R2 have abovementioned values. Invention provides the development of a method for unimpeded preparing 1-(2-benzothiazolyl)-alkylamine derivative, i. e. substituted alkylamine derivative from the 2-aminothiophenol derivative with the satisfactory industrial yield and without pollution of the environment.

EFFECT: improved preparing method, valuable properties of compound.

8 cl, 13 ex

 

The technical field

The present invention relates to a method for producing substituted alkylamino derived, suitable as intermediate substances for medical or agricultural chemical reagent. In particular the present invention relates to a method for producing substituted alkylamino derivative or its acid additive salt of 2-aminothiophenol derived under satisfactory industrial output.

1-(2-benzothiazolyl)alkylamine derivatives known as substituted alkylamine derivatives, each of which has a condensed heterocyclic ring. As a method of synthesis known to the condensation reaction between 2-aminothiophenol derivative and N-carboxyanhydrides amino acid (see JP-A-8-325235). This method, however, had problems, consisting in the fact that certain compounds, such as (RS)-1-(6-fluoro-2-benzothiazolyl)ethyl amine and the like did not lead to a satisfactory output. This method had the additional problem, namely that 2-aminothiophenol derivative used as starting material, has a strong odor of hydrogen sulfide and volatile in the air, particularly fluoro-substituted 2-aminothiophenol derivative has a very strong smell and unstable to such an extent that the derivative is easily the image of the em disulfide, even when removing the air, and it is difficult to work in an industrial environment; however, the use of such connection is inevitable.

2-aminothiophenol derivative used as starting material in the above reaction, can be easily obtained with high yield by hydrolysis of substituted benzothiazole derivative with alkali metal hydroxide such as potassium hydroxide or the like; however, in this case, the product is obtained as a salt of an alkali metal and it is the main. Meanwhile, N-carboxyanhydride amino acids, used as starting material in the above reaction, is easily decomposed in the presence of alkali with obtaining the oligomer. Therefore, 2-aminothiophenol derived alkali metal salt synthesized in the above-described method, it is necessary to turn in a neutral or acidic. However, adding hydrochloric acid or the like in 2-aminothiophenol derived alkali metal salt to convert salt into the free 2-aminothiophenol derivative is formed disulfide, resulting in a very low yield of the desired product.

To improve the scheme described above tasks, it was found that 1-(2-benzothiazolyl)alkylamino derivative can be obtained with high yield by conversion of 2-aminothiophenol derived its salt meth is the lia (e.g., zinc salt), stable in air and odorless, the reaction of a metal salt with N-carboxyanhydrides and carrying out cyclization (see Published International Application WO 99/16759). In this method, however, remains a problem, in that a salt of a metal (e.g. zinc salt), obtained as a by-product, is mixed with waste water and disposal of wastewater leads to high overhead costs; to highlight 2-aminothiophenol derivative metal salt necessary filtering, drying and etc, and thus, the method is complicated and difficult to use in the industry.

The present invention is to develop a way to get 1-(2-benzothiazolyl)alkylamino derived, i.e. substituted alkylamino derived from 2-aminothiophenol derived under satisfactory industrial output without pollution, etc.

These applicants have conducted studies to solve the problems of the earlier technology. In the present applicants have paid attention to the transformation of 2-aminothiophenol derived in acidic and successfully found that 2-aminothiophenol derivative may be converted into acid without significant formation of disulfide addition of alkali metal salts of 2-AMI is ativanonline derived in acid. The present applicants have additionally found that although the reaction between the formed 2-aminothiophenol derivative and N-carboxyanhydrides amino acids requires the presence of acid, this reaction proceeds without the need to re-add the acid, if the reaction system is maintained acidic, if the salt of 2-aminothiophenol derived in advance is added to the acid, and the specified product can be obtained with high yield; that the reaction is highly favorable to the environment because it does not form a metal (e.g. zinc)containing waste water as a by-product in the reaction with N-carboxymethylaminomethyl does not require an organic solvent; and that the reaction can be conducted in a single vessel (one reactor) from operations add salt 2-aminothiophenol derivative to the acid until the reaction between 2-aminothiophenol derivative and N-carboxyanhydrides and its very easy to carry and so on. The above obtained data resulted in the implementation of the present invention.

The above object is achieved by the following inventions [1] to [8].

[1] a Method of obtaining substituted alkylamine derivative represented by the following General formula (3):

(in which X is a halogen atom, alkyl group,alkoxygroup, the cyano or nitro-group; n is an integer from 1 to 4; R1and R2each independently is a hydrogen atom or phenylseleno or unsubstituted alkyl group and may together form a 5 - or 6-membered cycle, which involves adding salt 2-aminothiophenol derivative represented by the following General formula (I):

(in which X and n have the same meaning as above) in acid so that the pH of the reaction medium had a value of 6 or less and turn salt into the free 2-aminothiophenol derivative of General formula (1), and then introducing the reaction of 2-aminothiophenol derived N-carboxyanhydrides amino acids represented by the following General formula (2):

(in which R1and R2each has the same meaning as given above).

[2] the Method of obtaining substituted alkylamine derivative represented by the following General formula (3):

(in which X is a halogen atom, alkyl group, alkoxygroup, cyano or nitro-group; n is an integer from 1 to 4; R1and R2each independently is a hydrogen atom or phenylseleno or unsubstituted alkyl group and may together form a 5 - or 6-membered cycle),this method involves adding salt 2-aminothiophenol derivative, represented by the following General formula (1):

(in which X and n have the same meanings as defined above) in the acid to allow the system to have a pH of 6 or less and turn salt into the free 2-aminothiophenol derivative of General formula (1) and then enter into the reaction in water or water-organic solvent mixture 2-aminothiophenol derived N-carboxyanhydrides amino acids represented by the following General formula (2):

(in which R1and R2each has the same definition as above).

[3] the Method of obtaining substituted alkylamino derived according to [2], in which the reaction between the salt of 2-aminothiophenol derivative and N-carboxyanhydrides amino acids is carried out in acidic conditions.

[4] the Method of obtaining substituted alkylamino derived according to [3], in which the reaction between the salt of 2-aminothiophenol derivative and N-carboxyanhydrides amino acids is carried out at pH 6 or less.

[5] the Method of obtaining substituted alkylamine derivative according to [1] or [2], in which X is a halogen atom.

[6] the Method of obtaining substituted alkylamine derivative according to [1] or [2], in which X is a fluorine atom.

[7] the Method of obtaining substituted alkylamino production the CSOs according to [1] or [2], in which salt of 2-aminothiophenol is derived difenolnoj salt of an alkali metal.

[8] the Method of obtaining substituted alkylamine derivative according to [1] or [2], in which the salt of 2-aminothiophenol derivative obtained by hydrolysis benzothiazole derivative represented by the following General formula (4):

(in which X and n have the same meaning as above) a hydroxide of an alkali metal.

The present invention is described in detail below.

In this way, in the beginning, a salt of 2-aminothiophenol derivative represented by the General formula (1), add the acid to convert the salt into the free 2-aminothiophenol derivative of General formula (1) in acid. In this case, the pH of the reaction system is preferably supported at a 6 or less. Then to the resulting reaction mixture is added N-carboxyanhydride amino acids of General formula (2) for the reaction and obtain the given replaced alkylamino derivative represented by the General formula (3). In this case, the reaction system is preferably acidic, and more preferably while maintaining the reaction system at pH 6 or less.

Turning salt 2-aminothiophenol derived in a free 2-aminothiophenol derived in acid conveniently providingconvenient in the acid salt of 2-aminothiophenol derivative, represented by the General formula (1) (Sol in some cases, you may be in aqueous solution). This working method is characterized this way. Meanwhile, add the acid to the salt of 2-aminothiophenol derivative (salt in some cases, you may be in aqueous solution) is preferred because the output of a given product is extremely low in the subsequent reaction with N-carboxyanhydrides amino acids represented by the General formula (2) (see example comparison 1, described below).

Salt of 2-aminothiophenol derivative used as starting material in the present method can be any compound represented by the General formula (1). In the formula X is a hydrogen atom; a halogen atom including chlorine, fluorine, bromine and iodine; C1-6alkyl group with unbranched or branched chain, including methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, n-pentelow group, n-hexoloy group, etc.; alkoxygroup (alkoxy-o-group in which the alkyl fragment is described above alkyl group; a cyano or a nitro-group, and n is an integer from 1 to 4.

As examples of salts of 2-aminothiophenol derivative represented by the General Faure who Ulai (1), in which X and n are the same as described above, can be mentioned alkali metal salt of 2-aminothiophenol derivatives, such as potassium salt of 2-amino-6-portifino, sodium salt of 2-amino-6-chlorothiophenol, potassium salt of 2-amino-5-portifino, sodium salt of 2-amino-5-portifino, potassium salt of 2-amino-5-bromothiophene, potassium salt of 2-amino-5-chlorothiophenol, potassium salt of 2-amino-5-methylthiophenol, potassium salt 2-amino-5-methoxythiophene, potassium salt of 2-amino-4-portifino, potassium salt of 2-amino-4-chlorothiophenol, potassium salt of 2-amino-4-cyanothiophene, sodium salt of 2-amino-4-nitrothiophene, potassium salt of 2-amino-4-methylthiophenol, potassium salt of 2-amino-4,5-Divertimento, potassium salt of 2-amino-3-portifino, potassium salt of 2-amino-3-bromothiophene, potassium salt of 2-amino-3-chlorothiophenol, potassium salt 2-amino-3-methylthiophenol and the like; ammonium salt 2-aminothiophenol derivatives, such as ammonium salt of 2-amino-5-portifino and the like; and organic amine salts of 2-aminothiophenol, such as triethylamine salt of 2-amino-5-portifino etc.

As salts of 2-aminothiophenol derived can also be used not only metal salts, for example salts of alkaline earth metals, group IIb. As such salts can be mentioned, for example, zinc salt of 2-amino-6-portifino, calcium salt 2-amine is-6-portifino and barium salt of 2-amino-6-portifino.

As salts of 2-aminothiophenol derived in the industry are commonly used salts of alkaline metal such as sodium salt, potassium salt, etc. and they are preferred from the viewpoint of the yield of a given product.

There are no particular restrictions on the method of obtaining salt 2-aminothiophenol derivative represented by the General formula (1). However, the salt of an alkali metal 2-aminothiophenol derivative can be easily obtained with a high yield according to, for example, the method described in JP-A-6-145158, by hydrolysis of the corresponding 2-aminobenzothiazole derivative with alkali metal hydroxide such as potassium hydroxide and the like, as shown in the following reaction formula:

(in which M is alkali metal and X and n have the same meaning as above). If the alkali metal hydroxide, such as sodium hydroxide, etc. is used instead of potassium hydroxide, can be obtained salt of an alkali metal 2-aminothiophenol derived that meet this metal.

In this way salt of 2-aminothiophenol derivative represented by the General formula (1)may be added to the acid aqueous solution obtained by hydrolysis of the corresponding 2-aminobenzothiazoles derived, by means of which m is tenderly to achieve a pH of the reaction system 6 or less. Thus, the present method provides a simple industrial process.

In the present method, as examples of the acid which is added salt of 2-aminothiophenol derivative represented by the General formula (1)can be cast mineral acid such as hydrochloric acid, sulfuric acid, bromatologia acid, phosphoric acid and organic acids such as p-toluensulfonate acid, methanesulfonate acid, triftormetilfullerenov acid, etc. These acids are preferably used in aqueous solution.

In the present method, the reaction system after adding salt 2-aminothiophenol derivative represented by the General formula (1), the acid is maintained at a pH of preferably 6 or less, more preferably 5 or less. Therefore, even if an aqueous solution, the hydrolysis of 2-aminobenzothiazoles derived, add itself to the acid, the amount of acid is determined, taking into account the amount of the main component (for example, a hydroxide of an alkali metal or ammonium, etc.)remaining in the aqueous solution obtained by hydrolysis, because of the acid, etc. whereby the pH of the reaction system is controlled at the level indicated above. The temperature at which salt of 2-aminothiophenol proizvodnog is, represented by the General formula (1), add the acid may be from -20 to 60°C, preferably from -5 to 40°C.

In the specific case of using, for example, potassium salt 2-aminothiophenol derived and concentrated hydrochloric acid pH of the reaction system is controlled at a given level, using 1 mole of the potassium salt of 2-aminothiophenol derivative and 1 mol or more, preferably 2 mol or more of hydrochloric acid.

In the subsequent reaction of the free 2-aminothiophenol derivative of General formula (1) with N-carboxyanhydrides amino acids represented by the General formula (2), an aqueous solution obtained by adding salt 2-aminothiophenol derivative represented by the General formula (1), in acid, can be used by itself.

N-Carboxyanhydride amino acids represented by the General formula (2)used in the present method can be any compound represented by the General formula (2). Amino acid fragment of the compounds represented by the General formula (2)may be optically active compound, a mixture in any proportions of the various optically active compounds or racemic modification. From the point of view of the stereochemistry of substituted alkylamino derivative obtained by the present method, the configuration and optical purity of amino acids, used the Oh as the starting material for obtaining N-carboxyanhydride amino acids of General formula (2), saved.

In the General formula (2) R1and R2represent a hydrogen atom or phenylseleno or unsubstituted alkyl group. An alkyl group can be a C1-6unbranched or branched alkyl group, and as specific examples are methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, n-pentelow group and n-hexoloy group. As an example phenylseleno alkyl group can be mentioned benzyl group. R1and R2may together form triamterenebuy group, tetraethylene group, etc. and can communicate with the amino acid basis with the formation of rings.

As N-carboxyanhydride amino acids represented by the General formula (2)with R1and R2note , for example, N-carboxyanhydride glycine, N-carboxyanhydride D,L-alanine, N-carboxyanhydride D-alanine, N-carboxyanhydride L-alanine, N-carboxyanhydride D,L-valine, N-carboxyanhydride D-valine, N-carboxyanhydride L-valine, N-carboxyanhydride D,L-phenylalanine, N-carboxyanhydride D-phenylalanine, N-carboxyanhydride L-phenylalanine, N-carboxyanhydride D,L-phenylglycine, N-carboxyanhydride D-phenylglycine, N-L carboxyanhydride-phenyl-gli is in, N-carboxyanhydride D,L-Proline, N-carboxyanhydride D-Proline, N-carboxyanhydride L-Proline, N-carboxyanhydride D,L-alanyl-N-methyl, N-carboxyanhydride D-alamin-N-methyl and N-carboxyanhydride L-alanine-N-methyl.

Used N-carboxyanhydride amino acids can be dried product or product wetted, for example, the reaction solvent (e.g. tetrahydrofuran)is used in obtaining, or an organic solvent used in its recrystallization, or a solution dissolved in tetrahydrofuran, acetonitrile or the like

There are no particular restrictions on the method of obtaining N-carboxyanhydride amino acids of General formula (2). The connection can be easily obtained according to, for example, the method described in J. Org. Chem., Vol.53, R (1988) reaction of the appropriate derived amino acid with phosgene.

In the reaction between the salt of 2-aminothiophenol derivative represented by the General formula (1), and N-carboxyanhydrides amino acids represented by the General formula (2), the number of N-carboxyanhydride amino acids ranges from 0.7 to 3 mol, preferably from 1.0 to 1.2 mol per mole of salt 2-aminothiophenol derivative represented by the General formula (1).

In the reaction of the acid can be added to control the pH of the system is equal to 6 or less. Examples of the acid is you, used therefore are mineral acids such as hydrochloric acid, sulfuric acid, bromatologia acid, phosphoric acid, etc. and organic acids such as p-toluensulfonate acid, methanesulfonate acid, triftormetilfullerenov acid and the like, the Amount of acid used therefore, can be any number up until the pH of the reaction system can be controlled preferably with 6 or less, more preferably 5 or less.

In the reaction, an aqueous solution of salts of 2-aminothiophenol derived can be used by itself as a solvent or may be added an organic solvent, miscible with water.

As miscible with water, the organic solvent used in the reaction, may be mentioned, for example, ether type organic solvents such as tetrahydrofuran, 1,4-dioxane and the like; nitrile type organic solvents such as acetonitrile and the like; amide type aprotic polar solvents, including N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, 1,1,3,3-tetramethylrhodamine etc.; sulfur-containing aprotic polar solvents, including sulfolan, dimethylsulfoxid etc.; hexamethylphosphoric triamide. Of these solvents, ether type organic solvents such as tetrahydrofuran, etc. and nitrile type organic solvents such as acetonitrile and the like are preferable.

These organic solvents may be used alone or in mixture of two or more types. If the melting point of the used solvent above the reaction temperature, it is preferable to use them in the form of a mixture, for example, amide type aprotic polar solvent.

The amount of organic solvent is from 0 to 20000 ml, preferably from 0 to 1000 ml per mol of salt 2-aminothiophenol derivative represented by the General formula (1).

In this regard, if miscible with water, an organic solvent, replace the non-polar or monopolarly organic solvent not miscible with water, such as chlorobenzene, uses a phase transfer catalyst and conduct a two-phase reaction, this reaction is adversely affecting the output; therefore, the holding of such a reaction is inappropriate.

The reaction temperature is from -50 to 60°C, preferably from -30 to 40°C. the reaction Time is usually 12 hours or less. The reaction is carried out by adding N-carboxyanhydride amino acid to the salt solution 2-aminothiophenol derivative represented on the soup formula (1), when a predetermined temperature under atmospheric pressure and stirring the mixture. Usually the application of pressure is not required.

The reaction mixture after the reaction process, if necessary, alkali, followed by extraction with an organic solvent, whereby the desired substituted alkylamine derivative can be easily selected. The addition of acids (mineral acids or organic acids may be selected salt of the desired substituted alkylamino derived. The example used for this mineral acid is hydrochloric acid, sulfuric acid, bromatologia acid and phosphoric acid; examples of organic acids are p-toluensulfonate acid, methanesulfonate acid and triftormetilfullerenov acid.

After completion of the reaction the desired substituted trialkylamine derivative is a salt form of the acid. Therefore, when salt (e.g. salt p-toluensulfonate acid, the desired product precipitates from the reaction system due to, for example, vysalivaniya, salt can be easily separated by filtration or the like, In this connection, it is also possible to easily select the desired substituted trialkylamine derived by adding to the reaction mixture after the reaction of an aqueous solution of alkali metal hydroxide (e.g. sodium hydroxide sludge is potassium hydroxide) to obtain the free amino group substituted alkylamino derived and then carrying out extraction with an organic solvent. When the desired substituted alkylamine derivative forms a salt with the acid and is dissolved, it is possible to remove salt in the aqueous salt solution or a solution of salt dissolved in a mixture of water-organic solvent.

As noted above, the relative stereochemistry of substituted alkylamino derived the reaction proceeds with retention of configuration and optical purity of the amino acid used as starting material to obtain N-carboxyanhydride amino acids.

As substituted alkylamine derivative represented by the General formula (3)obtained by the present method, may be mentioned, for example, (6-fluoro-2-benzothiazolyl) methylamine, (RS)-1-(2-benzothiazolyl)ethylamine, (R)-1-(2-benzothiazolyl)ethylamine, (S)-1-(2-benzothiazolyl)ethylamine, (RS)-1-(6-fluoro-2-benzothiazolyl)ethylamine, (R)-1-(6-fluoro-2-benzothiazolyl) ethylamine, (S)-1-(6-fluoro-2-benzothiazolyl)ethylamine, (R)-1-(4-chloro-2-benzothiazolyl)ethylamine, (R)-1-(5-chloro-2-benzothiazolyl)ethylamine, (R)-1-(6-chloro-2-benzothiazolyl)ethylamine, (R)-1-(-6-bromo-2-benzothiazolyl)ethylamine, (R)-1-(4-methyl-2-benzothiazolyl)ethylamine, (R)-1-(6-methyl-2-benzothiazolyl)ethylamine, (R)-1-(6-methoxy-2-benzothiazolyl)ethylamine, (R)-1-(5-cyano-2-benzothiazolyl)ethylamine, (R)-1-(5-nitro-2-benzothiazolyl)ethylamine, (RS)-1-(6-fluoro-2-benzothiazolyl)-2-methylpropylamine, (R)-1-(6-fluoro-2-benzothiazolyl)-2-methyl shall repellin, (S)-1-(6-fluoro-2-benzothiazolyl)-2-methylpropylamine, (RS)-1-(4-methyl-2-benzothiazolyl)-2-methylpropylamine, (R)-1-(4-methyl-2-benzothiazolyl)-2-methylpropylamine, (S)-1-(4-methyl-2-benzothiazolyl)-2-methylpropylamine, (PS)-1-(6-fluoro-2-benzothiazolyl)benzylamine, (R)-1-(6-fluoro-2-benzothiazolyl)benzylamine, (S) -1- (6-fluoro-2-benzothiazolyl) benzylamine, (RS)-2-(6-fluoro-2-benzothiazolyl)pyrrolidine, (R)-2-(6-fluoro-2-benzothiazolyl)pyrrolidin and (S)-2-(6-fluoro-2-benzothiazolyl)pyrrolidin.

Substituted alkylamine derivative represented by the General formula (3)obtained in this way, extreme useful as intermediate compounds for the production of the fungicide for agricultural and horticultural applications (see JP-A-8-176115).

The present invention will be further described more specifically based on examples.

Example 1

40 ml of water and 30 g (0,296 mol) of 36% hydrochloric acid were placed in a 300 ml flask as a reactor and cooled to 3°C. in Addition, precapitalism was added at 2 to 5°under stirring to 48.0 g (0,056 mol) of an aqueous solution of potassium salt of 2-amino-5-portifino, followed by stirring for 1 hour. The system had a pH of 5,23, in Addition, was added 9.7 g (0,051 mol) monohydrate p-toluensulfonate acid and 15 ml of tetrahydrofuran, followed by stirring for 30 minutes. In addition, it was added 8.1 g (by 0.055 mol) of N-carboxyanhydride-D-alanine (purity: 78,3 %) PR is 0° C. the resulting reaction mixture was stirred at 15 to 20°C for 18 hours. The obtained crystals were collected by filtration and dried at 60°to obtain 16.6 g of p-toluensulfonate [2-(6-fermentational)]ethylamine (purity: 93.5 per cent) (output accounted for 82.8% of in relation to the potassium salt of 2-amino-5-portifino).

Example comparison 1

48,2 g (0,056 mol) of an aqueous solution of potassium salt of 2-amino-5-portifino were placed in a 300 ml flask as a reactor and cooled to 1°C. in Addition, precapitalism added 72,0 g (0,296 mol) of 15% hydrochloric acid at from 0 to 5°with stirring, followed by stirring for 1 hour. The system had a pH of 5.40. In addition, it was added 9.7 g (0,051 mol) monohydrate p-toluensulfonate acid and 15 ml of tetrahydrofuran, followed by stirring for 30 minutes. In addition, it was added 8.1 g (by 0.055 mol) of N-carboxyanhydride-D-alanine (purity: 78,3%) at 0°C. the resulting mixture was kept at 15 to 20°C for 18 hours. The obtained crystals were collected by filtration and dried at 60°to obtain 12.2 g of p-toluensulfonate [2-(6-fermentational)]ethylamine (purity: 76,5%) (output amounted to 45.2% in relation to the potassium salt of 2-amino-5-portifino).

Example 2

80 ml of water and 60 g (0,592 mol) of 36 % hydrochloric acid were placed in a 500 ml flask as a reactor and cooled to 2°C. in Addition, precapitalism to allali at from 0 to 5° With under stirring for 96.1 g (0,112 mol) of an aqueous solution of potassium salt of 2-amino-5-portifino, followed by stirring for 1 hour. The system had a pH 5,02. In addition, it was added to 19.4 g (is 0.102 mol) monohydrate p-toluensulfonate acid and 25 ml of tetrahydrofuran, followed by stirring for 30 minutes. In addition, it was added 16.2 g (0,110 mol) of N-carboxyanhydride-D-alanine (purity: 78,3%) at 0°C. the resulting mixture was kept at 15 to 20°C for 18 hours. The obtained crystals were collected by filtration and dried at 60°obtaining 33,9 g p-toluensulfonate [2-(6-fermentational)]ethylamine (purity, 92.4 per cent) (output amounted to 75.6% in relation to the potassium salt of 2-amino-5-portifino).

Example 3

230,4 g of water and to 172.8 g (1,706 mol) of 36 % hydrochloric acid were placed in a 2-liter flask as a reactor and cooled to 3°C. in Addition, precapitalism added 276,5 g (0,315 mol) of an aqueous solution of potassium salt of 2-amino-5-portifino at from 0 to 5°with stirring, followed by stirring for 1 hour. Additionally added precapitalism to 15.8 g of 50% potassium hydroxide to set the pH of the system at 4,95. The curing was carried out for 1 hour. Then added of 56.4 g (0,296 mol) monohydrate p-toluensulfonate acid, followed by keeping 3°C for 30 minutes. In addition, added precapitalism when the t 16 to 19° Received in advance a solution of N-carboxyanhydride-D-alanine (46,8 g, purity: 78,3%, 0,318 mol)dissolved in tetrahydrofuran (73 ml). The curing was carried out at 15 to 20°C for 18 hours. The obtained crystals were collected by filtration and dried at 60°obtaining 96,6 g p-toluensulfonate [2-(6-fermentational)]ethylamine (purity: 93,76%) (yield was 78,0% compared to the potassium salt of 2-amino-5-portifino).

Example 4

80 ml of water and 60 g (0,592 mol) of 36 % hydrochloric acid were placed in a 500 ml flask as a reactor and cooled to from 0 to 2°C. in Addition, precapitalism added at from 0 to 5°under stirring 96,0 g (0,112 mol) of an aqueous solution of potassium salt of 2-amino-5-portifino. The resulting system had a pH of 0.90. Next were added to 20.0 g (0,105 mol) monohydrate p-toluensulfonate acid. In addition, precapitalism at 16 to 20°solution was added M-carboxyanhydride-D-alanine (16.7 g, purity: 78,3%, 0,318 mol)dissolved in tetrahydrofuran (30 ml) (solution prepared in advance with from 16 to 20°). The curing was carried out at 15 to 20°C for 4 hours. The obtained crystals were collected by filtration and dried at 60°obtaining 31,5 g p-toluensulfonate [2-(6-fermentational)]ethylamine (purity: 98,95%) (yield was 75.5% in relation to the potassium salt of 2-amino-5-portifino).

Example 5

Reactions were carried out in t is m the same scale and with the same operations, as in example 4, except that the pH of the reaction system after adding precapitalism potassium salt of 2-amino-5-portifino was established in 3,69, whereby received 30,6 g p-toluensulfonate [2-(6-fermentational)]ethylamine (purity: 98,84%) (output reached 73.1% compared to the potassium salt of 2-amino-5-portifino).

Example 2 comparison

Reactions were carried out in the same scale and with the same operations as in example 4, except that the pH of the reaction system after adding precapitalism potassium salt of 2-amino-5-portifino installed at 7.03, and the aging time was changed to 18 hours, whereby was obtained 27,0 g p-toluensulfonate [2-(6-fermentational)]ethylamine (purity: 19,59%) (yield was 12.8% compared to the potassium salt of 2-amino-5-portifino).

Example 6.

80 ml of water and 60 g (0,592 mol) of 36 % hydrochloric acid were placed in a 500 ml flask as a reactor and cooled to 0°C. in Addition, precapitalism added at from 0 to 5°under stirring 96,0 g (0,112 mol) of an aqueous solution of potassium salt of 2-amino-5-portifino followed by holding for 1 hour. The system had a pH of 1.26. In addition, precapitalism at 15 to 20°solution was added N-carboxyanhydride-D-alanine (16.7 g, purity: 78,3%, 0,318 mol)dissolved in 30 ml of acetonitrile (solution prepared beforehand by 15 to 20°). uderzhivanie was carried out at 15 to 20° C for 3 hours. The resulting system was subjected to separation of the phases at 40°With twice 50 ml of toluene. From the lower layer was obtained aqueous solution (concentration: 8,96%)containing 221,5 g of the hydrochloride [2-(6-fermentational)]ethylamine. The output amounted to 90.3% in relation to the potassium salt of 2-amino-5-portifino.

Example 7.

80 ml of water and 60 g (0,592 mol) of 36 % hydrochloric acid were placed in a 500 ml flask as a reactor and cooled to 0°C. in Addition, precapitalism added at from 0 to 5°under stirring 96,0 g (0,112 mol) of an aqueous solution of potassium salt of 2-amino-5-portifino followed by holding for 1 hour. The system had a pH of 1.54. In addition, precapitalism at 15 to 20°solution was added N-carboxyanhydride-D-alanine (16.7 g, purity: 78,3%, 0,318 mol)dissolved in 30 ml of tetrahydrofuran (solution prepared beforehand by 15 to 20°). The curing was carried out at 40°C for 2 hours. The resulting system was subjected to twice the separation of the phases at 40°With 50 ml of toluene. From the lower layer was obtained aqueous solution (concentration: 10,42%)containing 211,2 g of the hydrochloride [2-(6-fermentational)]ethylamine. The output amounted to 99.9% with respect to the potassium salt of 2-amino-5-portifino.

Example 8

In a 2000 ml flask as a reactor were placed 166,7 g of water, 589 g of 50% aqueous solution of potassium hydroxide (5,25 mol as KOH) and 168,2 g (1.00 mol) of 6-fluoro-2-am is nebensaison. They were heated, kept for 8 hours boiling under reflux at from 113 to 115°and then was cooled to 40°C. the resulting mixture was washed 311 g of toluene and then was subjected to separation of the phases to obtain 904,0 g of an aqueous solution of potassium salt of 2-amino-5-portifino (concentration: 20 %, output: 99,7 %). This aqueous solution of the potassium salt of 2-amino-5-portifino can be used to obtain p-toluensulfonate [2-(6-fermentational)]ethylamine or an aqueous solution of hydrochloride [2-(6-fermentational)]ethylamine as described in example 1-7.

Example 9

80 ml of water and 60 g (0,592 mol) of 36 % hydrochloric acid were placed in a 300 ml flask as a reactor and cooled to 3°C. in Addition, precapitalism was added at 2 to 5°with stirring 96 g (0,112 mol) of an aqueous solution of potassium salt of 2-amino-5-portifino, followed by stirring for 1 hour. The system had a pH of 5,23. In addition, there was added 20 g (0,105 mol) monohydrate p-toluensulfonate acid and 30 ml of tetrahydrofuran, followed by stirring for 30 minutes. In addition, it was added 16.7 g (0,114 mol) of N-carboxyanhydride-D-alanine (purity: 78,3%) at 0°C. the resulting mixture was kept at 15 to 20°C for 18 hours. The obtained crystals were collected by filtration and dried at 60°obtaining 36,0 g p-toluensulfonate [2-(6-fermentational the l)ethylamine (purity: 95.2 percent) (output accounted for 82.8% of in relation to the potassium salt of 2-amino-5-portifino).

Example 10

80 ml of water and 60 g (0,592 mol) of 36 % hydrochloric acid were placed in a 500 ml flask as a reactor and cooled to 2°C. in Addition, precapitalism added at from 0 to 5°under stirring for 96.1 g (0,112 mol) of an aqueous solution of potassium salt of 2-amino-5-portifino, followed by stirring for 1 hour. The system had a pH 5,02. In addition, it was added to 19.4 g (is 0.102 mol) monohydrate p-toluensulfonate acid and 25 ml of tetrahydrofuran, followed by stirring for 30 minutes. In addition, it was added 16.2 g (0,110 mol) of N-carboxyanhydride-D-alanine (purity: 78,3%) at 0°C. the resulting mixture was kept at 15 to 20°C for 18 hours. The obtained crystals were collected by filtration and dried at 60°With receipt of 30.9 g of p-toluensulfonate [2-(6-fermentational)]ethylamine (purity: 92%) (output amounted to 75.6% in relation to the potassium salt of 2-amino-5-portifino).

Example 11

80 ml of water and 60 g (0,592 mol) of 36 % hydrochloric acid were placed in a 500 ml flask as a reactor and cooled to from 0 to 2°C. in Addition, precapitalism added at from 0 to 5°under stirring 96,0 g (0,112 mol) of an aqueous solution of potassium salt of 2-amino-5-portifino. The system had a pH of 0.90. In addition, it was added to 20.0 g (0,105 mol) monohydrate p-toluensulfonate acid. Then a solution of N-carboxyanhydride-D-alanine (16.7 g, purity: 78,3%, 0,318 mol), rastvorennogo is in tetrahydrofuran (30 ml) (solution prepared in advance with from 16 to 20° C), added by precapitalism at 16 to 20°C. the Curing was carried out at 15 to 20°C for 4 hours. The obtained crystals were collected by filtration and dried at 60°to obtain 31.5 g of p-toluensulfonate [2-(6-fermentational)]ethylamine (purity: 98,95%) (yield was 75.5% in relation to the potassium salt of 2-amino-5-portifino).

Example 12

80 ml of water and 72 g (0,711 mol) of 36 % hydrochloric acid were placed in a 500 ml flask as a reactor and cooled to 0°C. in Addition, precapitalism added at from 0 to 5°under stirring 96,0 g (0,112 mol) of an aqueous solution of potassium salt of 2-amino-5-portifino followed by holding for 1 hour. The system had a pH of 1.26. In addition, added precapitalism at 15 to 20°With a solution of N-carboxyanhydride-D-alanine (16.7 g, purity: 78,3%, 0,318 mol)dissolved in 30 ml of acetonitrile (solution prepared beforehand by 15 to 20°). The curing was carried out at 15 to 20°C for 3 hours. The resulting mixture was subjected to separation of the phases at 40°With twice 50 ml of toluene. From the lower layer was obtained aqueous solution (concentration: 8,96%)containing 263,0 g of the hydrochloride [2-(6-fermentational)]ethylamine. The output amounted to 90.3% in relation to the potassium salt of 2-amino-5-portifino).

Example 13

80 ml of water and 72 g (0,711 mol) of 36 % hydrochloric acid were placed in a 500 ml flask as a reactor and cooled to 0&x000B0; C. in Addition, precapitalism added at from 0 to 5°under stirring 96,0 g (0,112 mol) of an aqueous solution of potassium salt of 2-amino-5-portifino followed by holding for 1 hour. The system had a pH of 1.54. In addition, added precapitalism at 15 to 20°With a solution of N-carboxyanhydride-D-alanine (16.7 g, purity: 78,3%, 0,318 mol)dissolved in 30 ml of tetrahydrofuran (the solution was prepared in advance with 15 to 20°). The curing was carried out at 40°C for 2 hours. The resulting mixture was subjected to separation of the phases at 40°With twice 50 ml of toluene. From the lower layer was obtained aqueous solution (concentration: 10,42 %)containing 251,1 g of the hydrochloride [2-(6-fermentational)]ethylamine. The output amounted to 99.9% with respect to the potassium salt of 2-amino-5-portifino.

Industrial applicability

The present invention relates to a method for producing substituted alkylamino derivative or salt additive acid, both of which are suitable as intermediate compounds used in medicine or chemistry of 2-aminothiophenol derived in the industry with high yield. In the present method can be used even fluoro-substituted 2-aminothiophenol derivative (compound easily forms a disulfide); since salt of metal (e.g. zinc) is not mixed with waste water, overhead costs at the waste utilization technologies wastewater is small; when removing the metal salt of 2-aminothiophenol derivative filtering and drying is not required; therefore, this method is extremely suitable for industrial production of substituted alkylamine derivative represented by the General formula (3)or its salt additive acid.

1. The method of obtaining substituted alkylamine derivative represented by the following General formula (3)

(3)

in which X is a halogen atom, alkyl group, alkoxygroup, cyano or nitro-group; n is an integer from 1 to 4; R1and R2each independently is a hydrogen atom or phenylseleno or unsubstituted alkyl group and may together form a 5-or 6-membered cycle,

which includes adding salt 2-aminothiophenol derivative represented by the following General formula (1)

in which X and n have the same values, which are presented above,

acid to allow the system to have a pH of 6 or less and turn salt into the free 2-aminothiophenol derivative of General formula (1) and then the introduction in the reaction of 2-aminothiophenol derived from amino-N-carboxyanhydrides represented by the following General formula (2):

(2)

in which R1and R2each has the same meaning as given above.

2. The method of obtaining substituted alkylamine derivative represented by the following General formula (3):

(3)

in which X is a halogen atom, alkyl group, alkoxygroup, cyano or nitro-group; n is an integer from 1 to 4; R1and R2each independently is a hydrogen atom or phenylseleno or unsubstituted alkyl group and may together form a 5 - or 6-membered cycle,

which includes adding salt 2-aminothiophenol derivative represented by the following General formula (1)

in which X and n have the same meanings as defined above,

in the acid to allow the system to have a pH of 6 or less and turn salt into the free 2-aminothiophenol derivative of General formula (1) and then enter into the reaction in water or water-organic solvent mixture 2-aminothiophenol derived N-carboxyanhydrides amino acids represented by the following General formula (2)

(2)

in which R1and R2each has the same values, which are presented above.

3. The method of obtaining substituted alkylamino production is till p. 2, characterized in that the reaction between the salt of 2-aminothiophenol derivative and N-carboxyanhydrides amino acids is carried out in acidic conditions.

4. The method of obtaining substituted alkylamino derived under item 3, characterized in that the reaction between the salt of 2-aminothiophenol derivative and N-carboxyanhydrides amino acids is carried out at pH 6 or less.

5. The method of obtaining substituted alkylamino derived under item 1 or 2, wherein X is a halogen atom.

6. The method of obtaining substituted alkylamino derived under item 1 or 2, wherein X is a fluorine atom.

7. The method of obtaining substituted alkylamino derived under item 1 or 2, characterized in that the salt of 2-aminothiophenol is derived difenolnoj salt of an alkali metal.

8. The method of obtaining substituted alkylamino derived under item 1 or 2, characterized in that the alkaline salt of 2-aminothiophenol derivative obtained by hydrolysis benzothiazole derivative represented by the following General formula (4):

(4)

in which X and n have the same values, which are indicated in claim 1 or 2,

hydroxide of an alkali metal.



 

Same patents:

FIELD: medicine, organic chemistry.

SUBSTANCE: the present innovation deals with new benzothiazole derivatives and medicinal preparation containing these derivatives for treating diseases mediated by adenosine receptor A2.A.. The present innovation provides efficient treatment of the above-mentioned diseases.

EFFECT: higher efficiency of therapy.

14 cl, 354 ex

The invention relates to new derivatives of benzothiazole General formula (I) or its salt, where p denotes 1; X1and X2together form =O; R1denotes hydrogen, halogen, alkyl, alkoxy; R2denotes hydrogen; R3denotes a-Z4-R6, -Z13-NR7R8; Z4denotes a-Z11-C(O)-Z12-, -Z11-C(O)-O-Z12-; Z11and Z12represent a simple bond or alkylene; Z13denotes a-Z11-C(O)-Z12-; R4denotes hydrogen; R5denotes phenyl, substituted groups Z1, Z2selected from alkyl, halogen, nitro, -HE, hydroxyalkyl, -C(O)Z6, -C(O)OZ6-Z4-NZ7Z8where Z4represents a simple bond; biphenyl, substituted alkyl; naphthalenyl, which optionally can be substituted-HE; chinoline, substituted alkyl; heterocyclics; Z6denotes alkyl which may be optionally substituted by a group-Z4-NZ7Z8, morpholinium; Z7, Z8each independently represents alkyl; R6denotes alkyl optionally substituted by cyano, methoxy, phenyl, -Z4-NZ7Z8and so on; R7denotes hydrogen, alkyl; R8denotes alkyl, the long is Z4-NZ7Z8; and t

The invention relates to the production of derivatives of 3-amino-2-mercaptobenzoic acid of the formula I, in which X represents fluorine, n = 0 or 1, Z represents CO-a or CS-A1A represents hydrogen, halogen, OR1or SR2, A1denotes hydrogen or or1, R1and R2denote hydrogen, substituted or unsubstituted, saturated or unsaturated hydrocarbon radical with an open chain, containing not more than 8 carbon atoms; the interaction of the compounds of formula II in which T represents hydrogen, C1-C6alkyl, C3-C6alkenyl,3-C6quinil,3-C6cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl; with aqueous strong base

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to organic chemistry, in particular to the synthesis of substituted 6-hydroxybenzothiazole containing labile fragments

The invention relates to benzothiazole derivative that is highly effective as a medicinal product, namely, benzothiazole derivative, useful as a preventive and therapeutic agent for diseases in which the function of suppressing the production of leukotrienes and thromboxanes are effective

The invention relates to new derivatives of 2-aminobenzothiazole, and to their use in pharmaceutical compositions having activity against convulsions induced by glutamate

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing amido acid ester that is useful as an intermediate substance in synthesis of agrochemical preparation. Invention relates to amido acid ester represented by compound of the general formula (7): wherein A represents substituted or free lower alkylene group, and so on; R1 represents substituted or free lower alkyl group, and so on; R3 represents hydrogen atom or lower alkyl group. Method for preparing amido acid ester involves interaction of amino acid represented by compound of the general formula (1): in presence of water with halogenated carboxylic acid ester represented by compound of the general formula (2): wherein X represents halogen atom with formation of amide represented by compound of the formula (3): Then amide compound interacts with halogenated carboxylic acid ester represented by compound of the general formula (4): wherein R2 represents substituted or free lower alkyl group, and so on; X represents halogen atom with preparing carboxylic acid mixed anhydride represented by compound of the general formula (5): Then carboxylic acid mixed anhydride interacts with amine compound represented by compound of the general formula (6): A, R1 and R3 have the same values as given above; Het represents substituted of free heterocyclic group. Invention provides reducing economic indices of the process.

EFFECT: improved preparing method.

9 cl, 2 ex

The invention relates to new derivatives of asola General formula I, where R1and R2the same or different, each represents hydrogen, cycloalkyl and so forth, or R1and R2forming (a) a condensed ring, (b) or (C), which may be optionally substituted substituted lower alkyl, amino group and the like; R3, R6, R7, R8the same or different, each represents a hydrogen atom, and so on; R4represents a cyano, tetrazolyl, -COOR9and so on; R5represents a hydrogen atom or lower alkyl; D represents optionally substituted lower alkylene; X and Z are the same or different, each represents oxygen or sulfur, Y is-N= or-CH=; A is-B is-O-, -S-B-, -B-S - or-In-; represents the lowest alkylene or lower albaniles; n = 2

The invention relates to a method for producing derivatives of General formula (I), which allows to improve the yield of these products

The invention relates to the field exitlinks acids, in particular to the intermediate compounds - derivatives of 1-oxo-3H-phthalazine-1-acetic acid of General formula

< / BR>
(A) where R1-C1-C6-alkyl, and the method of obtaining derivatives complex alilovic esters of 4-oxo-3H-phthalazine-1-acetic acid of General formula

< / BR>
(I) where R1-C1-C6-alkyl, R2and R3may be the same or different and represent a hydrogen atom, chlorine or trifluoromethyl, which are inhibitors oldselected

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing amido acid ester that is useful as an intermediate substance in synthesis of agrochemical preparation. Invention relates to amido acid ester represented by compound of the general formula (7): wherein A represents substituted or free lower alkylene group, and so on; R1 represents substituted or free lower alkyl group, and so on; R3 represents hydrogen atom or lower alkyl group. Method for preparing amido acid ester involves interaction of amino acid represented by compound of the general formula (1): in presence of water with halogenated carboxylic acid ester represented by compound of the general formula (2): wherein X represents halogen atom with formation of amide represented by compound of the formula (3): Then amide compound interacts with halogenated carboxylic acid ester represented by compound of the general formula (4): wherein R2 represents substituted or free lower alkyl group, and so on; X represents halogen atom with preparing carboxylic acid mixed anhydride represented by compound of the general formula (5): Then carboxylic acid mixed anhydride interacts with amine compound represented by compound of the general formula (6): A, R1 and R3 have the same values as given above; Het represents substituted of free heterocyclic group. Invention provides reducing economic indices of the process.

EFFECT: improved preparing method.

9 cl, 2 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing a substituted alkylamine derivative from the 2-aminothiophenol compound with high industrial yield that can be used as an intermediate compound used in medicine or in agriculture. Invention proposes a method for preparing substituted alkylamine derivative represented by the following general formula (3): wherein X mean halogen atom, alkyl group, alkoxy-group, cyano-group or nitro-group; n means a whole number from 1 to 4; each R1 and R2 means independently hydrogen atom of phenyl-substituted, or unsubstituted alkyl group that can in common form 5- or 6-membered cycle, or its additive acid salt. Method involves addition of 2-aminothiophenol derivative salt represented by the following formula (1): wherein X and n have abovementioned values to acid to provide pH value 6 or less and to convert salt to free 2-aminothiophenol derivative of the general formula (1) followed by addition of 2-aminothiophenol derivative with amino-N-carboxyanhydride to the reaction represented by the following general formula (2): wherein each R1 and R2 have abovementioned values. Invention provides the development of a method for unimpeded preparing 1-(2-benzothiazolyl)-alkylamine derivative, i. e. substituted alkylamine derivative from the 2-aminothiophenol derivative with the satisfactory industrial yield and without pollution of the environment.

EFFECT: improved preparing method, valuable properties of compound.

8 cl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein A means benzene ring optionally substituted with one or more the following groups: -OR2 wherein R2 mean linear or branched (C1-C5)-alkyl; X means -CH=, -CH2-, -N= or -NH-radical; Y means radical -CH2, oxygen or sulfur atom or group -NR7 wherein R7 means hydrogen atom or linear or branched (C1-C5)-alkyl; R1 means hydrogen atom, linear or branched (C1-C5)-alkyl, and to pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition showing anti-diabetic activity. The pharmaceutical composition comprises compound of the general formula (I) as an active component and an inert excipient. Invention provides bicyclic derivatives of guanidine eliciting anti-diabetic activity.

EFFECT: valuable medicinal properties of compounds and composition.

8 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula

, where R1 is a

or or or group, R2 is morpholine or OR' or N(R")2; R' is a lower alkyl, a lower alkyl substituted with a halogen, or -(CH2)n-cycloalkyl; R" is a lower alkyl; R is NO2 or SO2R'; R4 is hydrogen, hydroxy, halogen, NO2, lower alkoxy, SO2R' or C(O)OR"; R5/R6/R7 denote hydrogen, halogen, lower alkyl; X'/X1 denote CH or N, provided that X1 /X1' are not CH at the same time; X2 is O or S; n equals 0 or 1, and to their pharmaceutically active acid-addition salts. The invention also relates to a drug.

EFFECT: obtaining novel biologically active compounds which are active as glycine transporter 1 inhibitors.

11 cl, 24 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent having CXCR2 inhibiting properties. In formula I , X denotes -CR3=CR4-, -CR5=N-, -N=CR6-, -NR7- or -S-; R3, R4, R5 and R6 independently denote hydrogen, F, CI, Br, I; R7 denotes hydrogen; Y1, Y2, Y3 and Y4 independently denote -CR8- or nitrogen, provided that at least two of Y1, Y2, Y3 and Y4 denote -CR8-; where R8 denotes hydrogen, F, CI, Br, I; A denotes a cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms; a bicyclic partially saturated 9-member cycloalkyl; a bicyclic partially saturated 9-10-member heterocycle in which two atoms in the ring are oxygen atoms; phenyl; naphthyl; a 5-6-member heteroaryl in which 1-3 atoms in the ring are oxygen, sulphur and nitrogen atoms; a 9-10-member bicyclic heteroaryl in which 1-3 atoms in the ring are nitrogen, oxygen and sulphur atoms; a 6-member heterocycle in which one atom in the ring is a nitrogen atom and which can be unsubstituted or substituted with alkyl having 1, 2, 3 or 4 carbon atoms, -C(O)CH3, -C(O)CH2CH3, -C(O)cyclopropyl, -C(O)CF3 and -C(O)OC(CH3)3; where phenyl, heterocyclic or heteroaryl radical is substituted with 1, 2 or 3 radicals selected from a group consisting of F, O, Br, I, OH, CN, NO2, SCF3, SF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; cycloalkyl having 3, 4, 5 or 6 carbon atoms; alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -S-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -NR9R10, C(O)R44, S(O)SR47, -(CH2)k-phenyl, 5-6-member heteroaryl, in which 1-3 atoms in the ring are nitrogen and sulphur atoms; where the phenyl radical may be substituted with F, CI, Br, I; R9 is an alkyl having 1, 2, 3 or 4 carbon atoms; R10 is an alkyl having 1, 2, 3 or 4 carbon atoms; R44 is an alkyl having 1, 2, 3 or 4 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; alkoxy having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms; R47 is an alkyl having 1, 2, 3 or 4 carbon atoms; k equals 0, 1, 2 or 3; s equals 1 or 2; B is -O-C(R11R12), -C≡C-, -CR52=CR53-, -C(R13R14)C(R15R16), -NR17-C(R18R19); R11, R12, R13, R14, R15, R16, R17, R18, R19, R52, R53 independently denote hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; D is C(O)OH, C(O)NHR21 or C(=NR58)NHR22; R21 and R22 independently denote hydrogen, -SO2-alkyl having 1, 2, 3 or 4 carbon atoms, -SO2-phenyl; R58 is OH; R1 and R2 independently denote an alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where the alkyl radicals are unsubstituted or substituted with 1 radical selected from a group consisting of F, Cl, Br, I, phenyl substituted with OH; or R1 and R2, taken together with a carbon atom with which they are bonded form a 3-, 4-, 5- or 6-member carbocycle. The invention also relates to use of formula I compounds in preparing a medicinal agent which has CXCR2 inhibiting properties, to a medicinal agent which containing an effective amount of the disclosed compound and having CXCR2 inhibiting properties, as well as to use of formula II compounds (formula and values of radicals are given in the formula of invention) in preparing a medicinal agent having CXCR2 inhibiting properties.

EFFECT: high effectiveness of application.

10 cl, 384 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R denotes a substituted or unsubstituted thiazolyl group of formula or ; R4 and R5, each independently, are selected from i) hydrogen; ii) a substituted or unsubstituted C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl; iii) a substituted or unsubstituted phenyl; iv) a substituted or unsubstituted heteroaryl containing 5 or 6 ring atoms and 1 or 2 heteratoms, where the heteroatoms are selected from nitrogen, oxygen, sulphur and combination thereof; or R4 and R5 can be taken together to form a saturated or unsaturated ring, having 5-7 atoms; said substitutes are independently selected from one or more groups, selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R6 denotes a group selected from i) hydrogen; ii) a substituted or unsubstituted C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl; iii) a substituted or unsubstituted phenyl or iv) a substituted or unsubstituted heteroaryl containing 5 or 6 ring atoms and 1 or 2 heteroatoms, where the heteroatoms are selected from nitrogen, oxygen, sulphur and combination thereof; where said substitutes are independently selected from one or more groups selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R1 is selected from i) hydrogen; ii) C1-C6 linear or C3-C6 branched alkyl; iii) a substituted or unsubstituted phenyl or iv) a substituted or unsubstituted benzyl; where said substitutes are independently selected from one or more groups selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R2 is selected from i) C1-C6 linear or C3-C6 branched alkyl or ii) C1-C6 linear or C3-C6 branched alkoxy; R3 denotes hydrogen or C1-C4 linear or C3-C6 branched alkyl.

EFFECT: compounds of formula (I) are effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

20 cl, 10 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula III or to its pharmaceutically acceptable salts, in which: R1 and R2 are independently selected from group, consisting of: (a) H, (b) (C2-C6)alkyl, (c) C1-C6 alkyl, interrupted by one or more groups -O-, (d) (C0-C3)alkyl-(C3-C7)cycloalkyl and (e) (CH2)nQ, where n=1-2 and where Q stands for aromatic ring system, which has from 5 to 6 ring atoms C, and Q can be independently substituted with groups up to 3 in number, selected from halogen, on condition that R1 and R2 simultaneously do not stand for H, and each alkyl of R1 and R2 can be independently substituted with one or more groups, selected from group, consisting of halogen, hydroxy, cyano, CF3 or C1-C4 alkyl, or R1 and R2 together with carbon, to which they are attached, form 3-7-member cycloalkyl or 6-member heterocycloalkyl ring, including one oxygen atom and which in case of necessity carries C1-C4 alkyl substituent, or R1 and R2 together with carbon, to which they are connected, form 3-7-member cycloalkyl ring, substituted with R20 and R21, and R20 and R21 together with carbon or carbons, to which they are connected, form 3-7-member cycloalkyl ring; R6 stands for C1-C6 alkyl; each R7 independently stands for C1-C6 alkyl; Y stands for -O-; R4 is selected from group, consisting of: (a) (C0-C3)alkyl-(C3-C7)cycloalkyl, (b) trifluoroethyl, and (c) trifluoropropyl; Z stands for phenyl or bicyclic ring system, which has 9 ring atoms, independently selected from C, N, O and S, on condition that not more than 3 ring atoms in any single ring differs from C, and said ring system can carry to 3 substituents, independently selected from group, consisting of R6, CF3 and SR6; and R5 is selected from group, consisting of NO2, NH2, F, Cl, Br, CN, SR6, S(O)2N(R7)2 and (C1-C4)alkyl, and each alkyl can be independently substituted with one or more halogens or CF3. Invention also relates to pharmaceutical composition for treatment of neurodegenerative disorder or improvement of cognitive function, containing therapeutically effective quantity of said compound; as well as to method of treatment of neurodegenerative disorder, for instance Alzheimer's disease, or improvement of cognitive function.

EFFECT: compounds act as modulators of gamma-secretase.

31 cl, 14 tbl, 3147 ex, 1 dwg

Up!