SU427514A3 - METHOD OF OBTAINING 3-GUANIDINOALKYL THIOPHENES - Google Patents

Description

one

The invention relates to a process for the preparation of previously unknown 3-guanidinoalkylthiophenes, which can be used as physiologically active preparations.

A known method for producing p-2-thienylalanine by the interaction of 2-phenyl-4- (2-phenylidene) -oxazolone with red phosphorus and hydrogen iodide in acetic acid.

A method for the preparation of 3-guanidinoalkylthiophenes of the general formula is provided.

SPN..L

 --RI

with II

- ®Re .... R5

where RiH.R2 is a hydrogen atom, a halogen or i is C-alkyl;

CiK4 is a hydrogen atom or Ci-C alkyl;

KB and Re is a hydrogen atom or Ci-Su-alkyl or Nb-and Re together is an alkylene group containing up to 7 carbon atoms, by means of which the nitrogen atoms bound to it are separated by at least two carbon atoms;

n 1-4,

or their salts, which consists in the fact that 3-aminoalkylthiophene of the general formula

St, Ngp-1 N-B5

At ri

where RI, R2 and Ra are as defined above, or a salt thereof, is reacted with a compound of the formula

ten

/ Ra

Y-C-NC

 Re n-x15

where R4 and Rs are as defined above;

X is the residue of Rg;

Y is alkyl mercapto, alkoxy or alkyl 2 Q amino group, the alkyl residue which contains

1-7 carbon atoms, amino group or pyrale residue, or X and Y together with the residue

C.N-denotes a nitrile group,

25 or /. Its salt, followed by separation

HefleBqro product by known methods in the video. Of a racemic mixture or individual optical isomers, which, if necessary, are separated and converted into free base or salt.

As acids for preparing salts of 3-guanidinoalkiltiofenov used are inorganic or organic carboxylic acids or sulfonic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, formic, acetic, succinic, malic, ascorbic, pyruvic, benzoic, anthranilic , salicylic, methanesulfonic, toluenesulfonic, sulfanilic acid, or amino acids, such as methionine, tryptophan, lysine, arginine.

Example 1. A mixture of 6.78 g of 3-tenylamine, 8.34 g of 2-methyl-2-isothiourea hemisulfate and 65 ml of water is heated for 6 hours at 100 ° C, then stirred for 5 hours at room temperature and maintained for 2 days at room temperature. The solvent is then distilled off in vacuo, and the residue is treated with ethanol and recrystallized from methanol-ethanol. Get hemisulfate 3-tenilguanidina, so pl. 197-198 ° C.

Purified 3-tenylamine is obtained as follows.

A mixture of 50 g of 3-methylthiophene, 150 ml of benzene and 1 g of benzoyl peroxide is boiled under reflux with stirring, then a mixture of 81.2 g of N-bromosuccinimide and 1 g of benzoyl peroxide is added over 12 minutes and stirred for another 4 minutes. The reaction mixture is then cooled in an ice bath, the precipitate is filtered off, the residue is washed with benzene and the filtrate is evaporated. The residue is distilled and the fraction boiling at 68-77 ° C / 2.2 mm Hg is collected. Art., representing 3-tenilbromid.

A solution of 5 g of 3-centilbromid in 5 ml of dimethylformamide is added dropwise to a mixture of 5.7 g of potassium phthalimide and 20 ml of dimethylformamide with stirring under nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature, after which 75 ml of chloroform was added and the mixture was poured into 100 ml of water. The organic phase is separated and the aqueous layer is extracted with chloroform. The combined organic solutions are washed with 80 ml of 2N. an aqueous solution of sodium hydroxide, dried, filtered and evaporated in vacuo. The residue is treated with diethyl ether. Get Y- (3-tenil) -phthalimide, so pl. 130-132 ° C.

A mixture of 85.4 g of M- (3-tenyl) -phthalimide, 50 ml of hydrazine hydrate and 1500 ml of methanol was boiled for 3.5 hours with stirring under reflux and during this time it was diluted with 100 ml of methanol. The reaction mixture is cooled, adjusted to pH 2 with concentrated hydrochloric acid and then boiled for 1.5 hours under reflux. After cooling, the mixture is filtered, the residue is washed with methanol and the filtrate is evaporated in vacuo. The residue is treated with water, the mixture is filtered, the filtrate is alkalinized with 6 n. aqueous sodium hydroxide solution and saturated with sodium carbonate. The reaction mixture is extracted with diethyl ether, the extract is dried, filtered, evaporated and the residue is distilled. Collect the fraction boiling at 65-67 ° C / 3 mm Hg. Art., representing 3-tenylamine.

Example 2. A mixture of 6.78 g of 3-tenylamine, 9.9 g of hemisulfate 2-methylmercaptoimidazoline and 65 ml of water is heated for 6 hours with stirring and incubated overnight

at room temperature. The solvent is then distilled off, the residue is dissolved in hot methanol, the solution is filtered and the filtrate is diluted with isopropanol. The precipitate obtained after cooling with ice is filtered off.

treated with ethanol and recrystallized from methanol-isopropanol. Get hemisulfate 1- (3-tenil) -2,3-ethyleneguanidine, so pl. 183-189 ° C. Example 3. A mixture of 3g (2-amino-ethyl) thiophene, 3.3 g of 2-methyl-2-isothiourea hemisulphate and 30 ml of water is stirred for 6 hours at 100 ° C and then for 5 hours at room temperature. The reaction mixture is incubated overnight at room temperature,

the solvent is then distilled off in vacuo. The residue is treated with isopropanol and recrystallized from methanol-ethanol. Get hemisulphate 2- (3-thienyl) ethylguanidine, so pl. 142-145 ° C.

The original 3- (2-amino-ethyl) -thiophene was prepared as follows.

To a mixture of 7.35 g of sodium cyanide and 50 ml of dimethylformamide, a solution of 17.7 g of 3-tenyl bromide in 10 ml of dimethylformamide was added over 10 minutes. The reaction temperature in this case rises to 55 ° C and is maintained by cooling at 40 ° C. Upon completion of the addition of the reagent, the mixture is heated for 1 hour at 70 ° C. The cooled reaction mixture is poured into 150 ml of water, then extracted with diethyl ether, the extract is washed with water, dried, filtered and evaporated. The resulting oil is distilled in vacuo. Receive (Z-thienyl) -acetonitrile, which boils at 82-93 ° C / 2 mm Hg. Art.

To a mixture of 5.55 g of (3-thienyl) acetonitrile and 40 ml of tetrahydrofuran, 60 ml of a 1M solution of diborane in tetrahydrofuran are added dropwise at 20 ° C. The reaction mass is stirred

3 hours at room temperature, decomposed by carefully adding 15 ml of ethanol and then acidified with hydrochloric acid in acetic ester. The mixture is stirred for 1 hour, the solid is collected on a filter, washed with acetic ester and dried. Get 3- (2-aminoethyl) -thiophene hydrochloride, so pl. 210-212 ° C. The product was dissolved in water, 10 g of sodium carbonate was added to it, and the mixture was extracted with diethyl ether. The extract is dried, filtered and evaporated. Get the appropriate free base.

Example 4. A mixture of 3.2 g of 2,5-dimethyl-Ztenylamine, 3.17 g of hemisulfate 2-methyl-2 of isothiourea and 30 ml of water is heated for 6 hours

at. The reaction mixture was incubated overnight at room temperature, the precipitated product was isolated and treated with isopropanol. After recrystallization from methanol, 2,5-dimethyl-3-tepilylguanidine hemisulphate, m.p. 200-204 ° C.

The original 2,5-dimethyl-3-tenylamine was prepared as follows.

At a temperature of 0 ° C to 3 ° C, a solution of 20.2 g of chloromethyl methyl ether in 10 ml of glacial acetic acid is added to a solution of 22.4 g of 2,5-dimethylthiophene in 50 ml of glacial acetic acid over 15 minutes. The resulting solution is stirred for 30 minutes, warmed to room temperature and stirred for esh, e for 3 hours. The reaction mixture is poured into 300 ml of water and extracted four times with diethyl ether. The combined extracts are washed with water and aqueous sodium bicarbonate, dried, filtered and evaporated. The resulting oil is evaporated in vacuo. 2,5-dimethyl-3-chloromethylthiophene is obtained, which boils at 80-90 ° C / 2 mm Hg. Art.

A mixture of 14.9 g of 2,5-dimethyl-3-chloromethylthiophene, 17.6 g of potassium phthalimide and 75 ml of dimethylformamide is stirred for 20 hours at room temperature, then 75 ml of chloroform is added to it and poured into water. The layers are separated and the aqueous layer is extracted with chloroform. The extract is washed with 1N. an aqueous solution of sodium hydroxide and water, dried, filtered and evaporated. The residue is recrystallized from isopropanol. 2.5-dimethyl-3-phthalimidomethylthiophene are obtained, m.p. 111-112 ° C.

A mixture of 19.5 g of 2,5-dimethyl-3-phthalimidomethylthiophene, 11 ml of hydrazine hydrate and 500 ml of methanol was refluxed for 3.5 hours, then cooled, acidified with 20 ml of hydrochloric acid and boiled for another 1 , 5 hours with reflux. After cooling, the reaction mixture is filtered, the residue is washed with methanol and the filtrate is evaporated at B-vacuum. The residue is dissolved in water, the mixture is filtered, the filtrate is alkalinized with 6N. aqueous sodium hydroxide solution and infused with sodium carbonate. The mixture is extracted with diethyl ether, the extract is dried, filtered and evaporated. The residue is distilled and the fraction boiling at 61–63 ° C / 1.2 mm Hg is collected. Art., representing 2,5-dimethyl-3-tenylamine.

Example 5. A mixture of 9.7 g of 2-bromo-3-tenilamia, 7.9 g of trimethylisothiouronium chloride and 160 ml of isopropanol was refluxed for 16 hours, after which the solvent was distilled off in vacuo. The residual oil is dissolved in 25 ml of water, the solution is made alkaline with 20 ml of a 50% aqueous solution of sodium hydroxide and extracted with toluene. The solvent is then distilled off in vacuo, and the residue is dissolved in 100 ml of isopropanol. The resulting solution is neutralized 2.59 g

94.5% aqueous solution of sulfuric acid and cool. The precipitate formed is filtered off and washed with cold isopropanol. After recrystallization from an isopropanol water mixture, 1 - (2-bromo-3-tenyl) -2,3-dimethylguanidine hemi-sulfate monohydrate is obtained, mp 277 ° C.

Example 6. Analogously to the previous examples, hemisulphates are also obtained:

1- (3-tenyl) -2,3-dimethylguanidine, so pl. 271-272 ° C (decomp., From a mixture of methanol-isopropanol); m.p. hemihydrate 262 ° C (decomp.);

1- (2,5-dichloro-3-tenil) -2,3 - dimethylguanidipa, so pl. 280 ° C (decomp., Out of water);

(3-thienyl) -ethyl -2,3 - dimethylguanidine, so pl. 196-200 ° C (decomp., From a mixture of methanol-isopropanol);

1- (3-tenyl) -2,3-diethylguanidine, so pl. 212- 213 ° С (from ethanol-methanol mixture);

(3-thienyl) -ethyl -2,3 - dimethylguanidine, so pl. 180-182 ° C (decomp., From a mixture of methanol-isopropanol);

1- (2,5 - dimethyl - 3-thienyl) -2,3 - dimethylguanidine, so pl. 290 ° C (decomp., From a mixture of methanol-isopropanol).

Example 7. A mixture of 25 g of 2-chloro-3-tenilamp, 43.5 g of trimethylisothiouronium chloride and 250 g of isopropanol was boiled under reflux for 16 hours and evaporated in vacuo. The residue is dissolved in 150 ml of water and the solution is alkalinized with ice-cooling with 25 ml of a 50% strength aqueous solution of caustic soda. The mixture is extracted with diethyl ether, the extract is evaporated and the residue is dissolved in 200 ml of isopropanol. The solution is neutralized with a 95% solution of sulfuric acid, the mixture is cooled to 0 ° C, filtered and the precipitate washed with isopropanol. The product is recrystallized from aqueous isopropanol. Get 1- (2-chloro-3-tepil) 2, 3-dimethylguanidip hemisulphate, so pl. 283 ° C (decomp.).

The starting 2-chloro-3-tenylamine was prepared as follows.

A solution of 20 g of 2-chloro-3-methylthiophene in 100 ml of carbon tetrachloride is reacted by moving 55 ° C with a mixture consisting of 30 g of N-bromo succinimide, 1 g of benzoyl peroxide and 50 ml of carbon tetrachloride. The reaction mixture is heated to reflux until the color changes and the decrease in foaming, then rapidly cooled to 20 ° C and filtered. The residue is washed with carbon tetrachloride and the filtrate is evaporated in vacuo. 2-chloro-3-tenilbromide is obtained.

A solution of 42 g of 2-chloro-3-tenyl bromide in 175 ml of chloroform and 21 ml of dimethylformamide is reacted with 80 g of potassium phthalimide and the mixture is stirred for 2 days at 55 ° C, then cooled to 20 ° C, dissolved in 200 ml of chloroform and 200 ml of water, the aqueous layer is separated and extracted with 150 ml of warm chloroform. The combined extracts are washed with water, dried and evaporated in vacuo.

The residue is dissolved in 80 ml of isopropanol and the solution is kept overnight in a refrigerator. The precipitate is filtered off, washed with isopropanol and from it, cleared with charcoal, recrystallized. Get N- (2-chloro-3-tenil) -phthalimide.

A mixture of 22 g of the obtained compound, 11.1 ml of hydrazine hydrate and 120 ml of water was boiled under reflux for 5 hours and, after cooling, reacted with 20 ml of hydrochloric acid and refluxed for 3 hours. Then the reaction mass is cooled, filtered and the pH of the filtrate is adjusted to 12 with 50% aqueous sodium hydroxide solution. Next, the mixture is extracted with diethyl ether, the extract is dried and evaporated. The residue is distilled and the fraction boiling at 90 ° C / 1 mm Hg is collected. Art., which is 2-chloro-3-tenylamine.

Subject invention

The method of obtaining 3-guanidinoalkylthiophene General formula

 i; c-tj-i

eight

R, .... B

where Ri and R2 is a hydrogen atom, halogen or Ci-Cr-alkyl;

Rs and R4 is a hydrogen atom or Ci-Cr-alkyl;

Rs and Re is a hydrogen atom or Ci-Su-alkyl or Rs and Re together is an alkylene group containing up to 7 carbon atoms, by means of which the nitrogen atoms bound to it are separated by at least two carbon atoms;

n 1-4,

or salts thereof, characterized in that the 3-aminoalkylthiophene of the general formula

(-n-CrNgg Nb, -RA II

HfB, S

g where Ri, R2 and Rs are as defined above, or its salt is reacted with a compound of the formula

/ Jr

0-n ii

N-i where R4 and Rs are as defined above;

X is the remainder of Re,

Y is an alkyl mercapto, alkoxy or alkylamino group, the alkyl residue of which contains

1-7 carbon atoms, amino group or pyrale residue, or X and Y together with the residue

C.N- denotes a nitrile group,

or its salt, followed by isolation of the target product by known methods in the form of a racemic mixture or individual optical isomers, as a free base or era of salt.