SU460619A3 - The method of obtaining - (aminophenyl) -aliphatic carboxylic acids - Google Patents

Description

where Xi is an amino group, R, Rj and Rz have the indicated meanings, they react with the glycol of formula III

SHE HE

or its reactive derivative.

The reaction is preferably carried out in the presence of water- or acid-binding agents, such as alkali metals or the corresponding alkoxides or carbonates.

The target products by known methods can be isolated in free form or in the form of the corresponding functional derivatives, in the form of the racemate or optically active isomers.

Example 1. A mixture consisting of 85.5 g of hydrochloric acid salt of a- (4-amino-3-3-chlorophenyl) propionic acid ethyl ester, 142 g of sodium carbonate and 600 ml of dimethylformamide is mixed with 107 g of 1.4- dibromo-2-butene, the latter being added dropwise, the reaction mixture is then boiled for 5 hours under reflux and then kept for 16 hours at room temperature. After the completion of the reaction, the mixture is filtered, the filtrate is evaporated under reduced pressure, and the residue after evaporation is stirred with hexane and filtered. The product remaining on the filter is washed with petroleum ether. The filtrate is evaporated and the residue after evaporation, containing a-3-chloro-4- (3-pyrrolin-1-yl) -phenyl propionic acid ethyl ester of the formula

ABOUT

l / -CH-d-O-d Hs

sn.

C1

280 ml of a 25% aqueous solution of sodium hydroxide are treated and the mixture is boiled for 8 hours under reflux. After cooling, the reaction mixture is diluted with water and washed with ether. The pH of the aqueous phase is adjusted to 5-5.2 by addition of hydrochloric acid, and then the product is extracted with ether. The organic extract is dried, filtered and and evaporated, and the residue after evaporation is recrystallized from a mixture of benzene and hexane. As a result of the operations carried out, a-3-chloro-4- (3-pyrrolin-1-yl) phenyl-propionic acid with m. Pl. 94-96 ° and the corresponding formula

(i

dH,

The original compound is prepared by the following method.

A solution of 52 g of 4-nitrophenylacetic acid ethyl ester in 350 ml of a mixture containing dimethylformamide and toluene in a 1: 1 ratio is mixed in small portions with stirring and cooling with 9.5 g of a 50% suspension of sodium hydride in mineral oil. After the mass was stirred for one and a half hours at room temperature, 26 g of methyl iodide was added dropwise to it at room temperature and the reaction mixture was stirred for 16 hours at room temperature. Water was then carefully added to the reaction mixture and extracted with ether. The organic extract is dried, filtered and the solvent evaporated. The residue after evaporation is taken up in 100 ml of ethyl alcohol and the crystal of the starting compound is added to the solution, after which the solution is placed in a refrigerator to crystallize the product. The crystallized precipitate is filtered off and the filtrate is evaporated. The residue is a- (4-pitrophenyl) propionic acid ethyl ester.

A mixture of 50 g of a- (4-nitrophenyl) -propionic acid ethyl ester in 200 ml of 95% aqueous ethyl alcohol is hydrogenated in the presence of 0.4 g of catalyst, which is palladium on carbon, until the absorption of hydrogen ceases. The reaction mixture is filtered and the filtrate is evaporated. As a result of the operations, a- (4-aminophenyl) propionic acid ethyl ester is obtained, m.p. hydrochloric acid salt of which is 137-140 °.

A mixture of 25 g of a (4-aminfeiyl) propionic acid ethyl ester and 100 ml of acetic anhydride prepared with stirring and cooled is left to stand at room temperature for 1 h, and then the mixture is evaporated under reduced pressure. The residue after evaporation is recrystallized from ether. As a result of the operations, a- (4-acetylaminophenyl) propionic acid ethyl ester is obtained, mp. which was 88-90 °.

Chlorine gas is bubbled through a solution of 25 g of a- (4-acetylaminophenyl) propionic acid ethyl ester by bubbles, and the chlorination process is controlled by thin-layer chromatography (silica gel: mixture of hexane and ether 1: 4). When the starting material is no longer detectable by thin layer chromatography, the mixture is evaporated under reduced pressure, the residue after evaporation is taken up with 150 ml of ethyl alcohol, and hydrogen chloride gas is passed through the solution for 45 minutes. The solution is then boiled for 15 hours under reflux and the solvent is then evaporated. The residue after evaporation is recrystallized from a mixture consisting of a mixture of ethyl alcohol and ether. As a result of the operations

get the hydrochloric acid salt of a- (4-amino-3-chlorophenyl) propionic acid ethyl ester with mp. 164-168 °.

The original connection can be obtained in the following way.

Through a mixture of 5000 ml of anhydrous ethyl alcohol and 1000 g of 4-aminophenylacetic acid, dry gaseous hydrogen chloride is passed under stirring for 5.5 h while stirring under reflux. Then, after holding for 16 hours at 10 ° C, the mixture is filtered, and the residue on the filter is washed with chilled anhydrous ethyl alcohol and then dissolved in 8000 ml of water. A 50% aqueous solution of sodium hydroxide is added to the resulting solution in 50 ml portions with stirring until the mixture is alkaline, and then the reaction mixture is stirred at room temperature for 1 hour. time the residue is filtered and washed with water. As a result of the operations, 4-aminophenylacetic acid ethyl ester was obtained. 47-49 °.

A solution containing 200 g of 4-aminophenylacetic acid ethyl ester in 250 ml of acetic anhydride is allowed to stand for 10 minutes, and then the solution is poured, with stirring, into 1500 ml of a mixture of ice and water. The precipitate obtained is filtered and washed with water. In this way, 4-anethyl aminophenylacetic acid ethyl ester is obtained by the reaction with m.p. 75-78 °.

A solution of 170 g of ethyl 4-acetylamiophenylacetic acid ester in 25 ml of ether is added with stirring for 25 minutes to a mixture consisting of 20.38 g of sodium, 2000 ml of anhydrous ammonia and iron nitrate hydroxide (P1) crystals. Then a mixture consisting of 120.28 g of methyl iodide and 50 ml of ether is added dropwise to the reaction mixture over 2 minutes, and the mixture is stirred for 1 hour. After this, the reaction mixture is treated with 50 g of ammonium chloride, then evaporated and the residue is treated with ether and a dilute aqueous solution of sodium hydroxide. The basic solution is extracted with ether and the combined organic solutions are evaporated. As a result of the operations carried out, ethyl a- (4-apethylaminophenyl) propionic acid is obtained, mp. 84-86 °. Approximately 90% of the obtained product is distilled in a special device with a small nozzle; a fraction is collected at 170-183 ° C at 0.15 mm Hg. Art.

The solution obtained by dissolving 72 g of a- (4-acetylaminophenyl) propionic acid ethyl ester in 200 ml of acetic acid is treated with chlorine gas, which is passed through the solution with stirring at 15-20 °. Reaction course

monitored by toicolysis chromatography, using a mixture of ether and hexane in the 4: 1 ratio as the mobile phase, in which the reaction product has Rf 0.8 and the starting material has Rf 0.51. After chlorination is complete, the reaction mixture is evaporated and the residue is distilled. Fraction, kinsch at 155-160 ° at 10 mm Hg. Art. is a (4-acetylamino-3-chlorophenyl) propionic acid ethyl ester.

A mixture prepared from 60 g of a- (4-acetylamino-3-chlorophenyl) propionic acid ethyl ester and 200 ml of ethyl alcohol,

saturated with gaseous hydrogen chloride, and the reaction mixture is boiled for 1 h under reflux. Then the reaction mixture is evaporated under reduced pressure. The residue after evaporation is dissolved in an aqueous solution of sodium hydroxide, and the mixture is extracted with ether. The organic extract is evaporated, and the residue after evaporation is chromatographed on alumina, and the elution is carried out with a mixture consisting of

from cyclohexane and ethyl acetate, taken in a ratio of 95: 5. As a result of the operations, a- (4-amino-3-chlorophenyl) propionic acid ethyl ester is obtained, mp.

Example 2. To a solution prepared from 25.1 g of d,; -a-3-chloro-4- (3-pyrrolin-1-yl) feiyl propionic acid, which is obtained by the method described in Example 1, and

450 ml of ether; 17.1 g of c1-a- (1-naphthyl) ethylamine are added with stirring. The reaction mixture is evaporated under reduced pressure, and the residue after evaporation is recrystallized seven times from ethyl acetate.

alcohol and cipher ether. A solution of 5 g of the salt obtained in this way, having a m.p. 133-135 °, in a minimum amount of a 5% aqueous solution of sodium hydroxide, washed with ether. Using hydrochloric acid, the pH of the solution is up to 5.5 and then extracted with ether. The organic extract is dried, filtered and evaporated. As a result of the operations performed, 6-a-3-chloro-4- (3-pyrrolin-1-yl) -phenyl propionic acid is obtained, and + 34.8 ° (ethyl alcohol).

Examples: p 3. A mixture of 11.3 g of pure cis1, 4-dichloro-2-butene, 15.7 g of ethyl ether

a - (4 - amniphenyl) propionic acid,

100 ml of dimethylformamide and 10.6 g of sodium carbonate are heated under reflux for 5 hours with stirring, and then the reaction mixture is kept for 16 hours at room temperature. After that, the reaction mixture is filtered, the filtrate is evaporated under reduced pressure, and the residue containing ethyl ether (3-pyrrolin-1-yl) is phenyl propionic

acid corresponding to the formula

ABOUT

 CH-H-O-CgHs

Nz

The mixture is taken up in 260 ml of a 25% aqueous solution of sodium hydroxide and the mixture is heated to reflux for 8 hours. After cooling, the reaction mixture was diluted with water, washed with ether and the pH was adjusted to about 5 by adding hydrochloric acid. Directly thereafter, the mixture was extracted with ether, the resulting organic extract was dried and evaporated. The residue is distilled up recrystallized from ethyl alcohol. As a result of the operations carried out, a-4- (3-lyrrolin-1-yl) phenyl propionic acid is obtained with a mp. 197-199 ° and the corresponding formula

ABOUT

II

dH-d-oH tn-.

The original connection receive the following method.

A solution prepared from 52 g of 4-nitrophenylacetic acid ethyl ester and 350 ml of a mixture of dimethylformamide and toluene in a 1: 1 ratio is mixed in small portions with 9.5 g of sodium hydride 50% in mineral oil, the mixing wire t with stirring and cooling. After stirring for 1.5 hours at room temperature, 26 tons of methyl iodide were added in drops to the reaction mixture, after which the mixture was further stirred at room temperature for 16 hours. Immediately thereafter, water was carefully added to the reaction mixture, then extracted with diethyl. ether, the organic extract is dried, filtered and evaporated. The residue after evaporation is extracted with 100 ml of ethyl alcohol, the resulting solution is seeded by introducing crystals of the starting material into it and left to stand in a refrigerator to crystallize the reaction product. The precipitated crystalline precipitate is filtered off and the filtrate is evaporated. In this way, a (4- "itrophenyl) propionic acid ethyl ester is obtained.

A mixture of 50 g of a- (4-nitrophenyl) | propionic acid ethyl ester and 200 ml of 95% aqueous ethyl alcohol is hydrogenated in the presence of 0.4 g of palladium on carbon catalyst until the absorption of hydrogen ceases. After that, the reaction mixture is filtered and the filtrate is evaporated. As a result of the carried out hydrogenation, a- (4-aminophenyl) propionic acid ethyl ester is obtained, the soloxidic salt of which has a melting point of 200 mg. 137-140 ° C.

Example 4. A mixture prepared from 24 g of a- (4-amino-3-chlorophenyl) butyric acid ethyl ester, 21 g of sodium carbonate and 25 g of is-1,4-dichloro-2-butene in 250 ml of dimethylformamide, boil for 12 hours under reflux. After cooling, the reaction mixture was diluted with diethyl ether, filtered, and the resulting filtrate was evaporated. The residue obtained in the amount of Cg and containing a-3-chloro-4- (3-pyrrolin-1 -yl) -phenyl - butyric acid ethyl ester of the formula

ABOUT

 CH-C-OdsHs

C1

dissolved in 100 ml of ethanol and 20 ml of a 25% aqueous solution of sodium hydroxide. The mixture was heated under reflux for 6 hours and then evaporated under reduced pressure. The residue after evaporation is dissolved in water, the solution is washed with diethyl ether and the pH is adjusted to 5.5 by addition of hydrochloric acid. Immediately after this, the resulting solution was extracted with diethyl ether. The organic extract is dried and then evaporated, and the residue after evaporation is recrystallized from hexane. As a result of the operations performed, a-3-chloro-4- (3-pyrrolin-1-yl) -fe (Nile-butyl acid with mp 103-105 ° and corresponding to the formula

Example 5. A mixture consisting of 0.63 g of a. (4-amino-3-chlorophenyl) -a-cyclopropylacetic acid methyl ester methyl salt, 0.56 g of 1 is-1,4-dichloro-2-butene, 0.7 g

sodium carbonate and 50 ml of dimethylformamide, boil for 10 hours under reflux in a nitrogen atmosphere and stir for 2 days at room temperature, and then the reaction mixture is filtered. The filtrate is evaporated, the residue is dissolved in water and the solution is extracted with diethyl ether. The organic extract is evaporated under reduced pressure. The residue after evaporation containing ethyl

a-3-chloro-4- (3-pyrrolin-1-yl) -phenyl cc-cyclopropyl acetic acid ester, dissolved in 35 ml of ethyl alcohol. To the resulting solution was added 0.5 ml of water and 0.28 g of potassium hydroxide. The resulting mixture is boiled for 2 hours under reflux and then evaporated under reduced pressure. The residue after evaporation is dissolved in water, the solution is washed with diethyl ether, the pH is adjusted to 4-4.5 by adding hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic extract is dried and evaporated, and the residue is recrystallized from diethyl ether. As a result of the operations performed, c.- 3-chloro-4- (3-pyrrolin-1-yl) -phenyl-a-cyclopropylacetic acid with m.p. 152-156 ° and the corresponding formula

ABOUT

N J -CH-ii-oH

7 s

Original item

get the following way. ,

To a solution of 200 g of a-cyclopropylphenylacetic acid in 200 ml of trifluoroacetic acid, while stirring and cooling to approximately 3 ° C, is added a mixture of 73 ml of 707 aqueous aqueous nitric acid and 9.1 ml of 96% aqueous sulfuric acid acid. After 1.5 hours, the mixture was brought to room temperature, stirred for the next 3 hours, and then poured with stirring into consisting of 300 ml of water and 3200 g of ice. After that, the mixture is filtered, the filter residue is washed with 6000 ml of water and dried. The result is a 2: 1 mixture of a-cyclopropyl-a- (4-nitr: ofphenyl) acetic acid and a-cyclopropyl-a-2 {2-nitrophenyl) acetic acid.

50 g of this mixture, 5 g of a 10% catalyst representing palladium on coal and 550 ml of 95% aqueous ethyl alcohol are hydrogenated at atmospheric pressure to absorb 15,900 ml of hydrogen. After stopping the reaction, the mixture is filtered and the filtrate is concentrated. The precipitate released during storage in the refrigerator is separated and recrystallized once from ethyl alcohol. In this way, pure a- (4-amInophenyl) a-cyclopropylacetic acid is obtained.

10 g of a- (4-aminophenyl) -a-cycloprO: lacoacetic acid and 75 ml of methyl alcohol are shifted while cooling in an ice bath with a saturated solution of hydrogen chloride in methyl alcohol. 30 minutes after mixing, the reaction mixture is heated for 1 hour at 38 ° and then treated with 100 ml of water. Immediately after this, with cooling and stirring, 105 ml of a 20% aqueous solution of sodium hydroxide is added to the reaction mixture. The precipitate obtained is filtered off, washed with water and dried. As a result of the operations, methyl ether is obtained.

a- (4-aminophenyl) -a-cyclopropylacetic acid with t. pl. 68-69 °.

A mixture consisting of 12 g of a- (4-aminophenyl) cc-cyclopropylacetic acid methyl ester and 100 ml of acetic anhydride is heated for 1 h on a steam bath and then the reaction mixture is evaporated. The residue after evaporation is dissolved in benzene and the mixture evaporated again. As a result

get a- (4-acetylaminophenyl) -ccc-cyclopropylacetic acid methyl ester, m.p. 159-162 °.

To a solution of 1.6 g of a- (4-acetylaminophenyl) -a-cyclopropylacetic methyl ester

acids in 50 ml of acetic acid are added dropwise while moving 30 ml of a saturated solution of chlorine in acetic acid. The mixture is then evaporated under reduced pressure, and the residue after evaporation

dissolved in a double volume of benzene. The resulting mixture was evaporated to give a- (4-acetylamino-3chlorophenyl) a-cyclopropylacetic acid methyl ester as a residue.

Hydrogen chloride gas is passed through a solution containing 1.6 g of a- (4-acetylamino-3-chlorophenyl) -a-diclopropylacetic acid methyl ester in 200 ml of methyl alcohol for 15 minutes. The reaction mixture is then refluxed for 21 hours, then evaporated under reduced pressure. The residue after evaporation is dissolved in 6N. hydrochloric acid, the mixture is washed with diethyl ether

and the aqueous solution of sodium hydroxide, the pH of the mixture is adjusted to an alkaline reaction and then extracted with diethyl ether. The organic extract is dried and evaporated. The residue after evaporation is dissolved in diethyl ether and the solution is acidified with a solution of hydrogen chloride in ether. The separated precipitate is filtered off, whereby the hydrochloric acid salt of c- (4-amino-3-chlorophenyl) -a-cyclopropyl-acetic acid methyl ester is obtained.

Example 6. A mixture consisting of 5 H 3 H-chloro-4 .- (3-pyrrolin-1-yl) -phenyl propionic acid, 200 ml of 1,2-dichloroethane and

42.6 anhydrous disodium phosphate, treated for 40 min with stirring and at a temperature of from -5 ° to 0 ° with a solution of trifluorone acetic acid, obtained from 2.1 ml of 90% aqueous hydrogen peroxide and

12.6 ml of trifluoroxy acid anhydride and 50 ml of 1.2 dichloroethane. After 2 hours, 300 g of ice are added to the reaction mixture, the organic phase is separated, and the aqueous layer is extracted with methylene chloride. United

organic solutions are dried, filtered and concentrated. As a result of the operations performed, a-3-chloro-4- (pyrrolin-1-yl) -phen l-a-propionic acid N-oxide is obtained, with m. Pl. 140-142 ° corresponding to the formula

ABOUT

II

1 SNS

Example 7. The 1,4-dibromo-2-butene, respectively, cis-1,4-dichloro-2-butene used in examples I and 3 is replaced by 1,5-d. Bromo-2- [Pentene] and the reaction is carried out with a- (4-amino-3-chlorophenyl) propionic acid ethyl ester or with k- (4-aminophenyl), T1-propionic acid ethyl ester. The reaction gives ethyl eff. Cc-3-chloro-4- (1,2,5,6-tetrahydro-1-iiridyl) -phenyl propionic acid, respectively, ethyl ester, 2, b, 6-tetrahydro-1-pyridyl -phenyl nronionic acid. As a result of hydrolysis carried out, for example, using the methods described in examples 1 and 3, i.e., by treating with a 25% aqueous solution of sodium hydroxide, these esters give a-3-chloro-4- (1,2 , 5,6-tetrahydro-1pyridyl) -phenyl propionic acid.

Example 8. To a mixture consisting of 5.5 g of ethyl 4- (3-pyrrolin-1-yl) phenylacetic acid ethyl ester, 100 ml of dimethyl ethyl formamide and 100 ml of toluene, 1.25 g of 54% - suspension of sodium hydride in mineral oil. After that, the reaction mixture is additionally moved for 1.5 hours at room temperature. A solution of 6.8 g of methyl iodide in 25 ml of toluene is then added dropwise to the reaction mixture over a period of 20 minutes. The reaction mixture is stirred at room temperature for 16 hours and then evaporated under reduced pressure. The residue after evaporation, containing (3-pyrrolin-1-yl) -phenyl propionic acid ethyl ester, is dissolved in 75 ml of a 10% aqueous solution of potassium hydroxide, and the resulting mixture is heated for 2 h with a steam bath. Directly after this, the mixture is cooled, the pH is adjusted to a value of 5 by addition of hydrochloric acid and then extracted with diethyl ether, the organic extract is dried and then evaporated. The resulting concentrate is diluted with petroleum ether and the precipitate formed is filtered off. As a result of the operations carried out, a-H4- (3-pyrrolin-1-yl) -phenyl propionic acid is obtained, which, after recrystallization from ethyl alcohol, has a melting point of mp. 197-199 °.

The original substance receive the following method.

The mixture containing 10.8 g of the 4-amNophenylacetic acid ethyl ester, hydrochloric acid, 32.4 g of 1,4-dibromo-2-butene and 84 g of sodium hydrogen carbonate in 500 ml of dimethylformamide is boiled under stirring for 6 hours. with reflux, and then the reaction mixture is heated in a hot state; the resulting filtrate is evaporated under reduced pressure and the result is 4- (3-pyrrolin-1-yl) -phenylacetic acid ethyl ester, which is used without further purification.

5 Example 9. A suspension of 4.37 g of a-3-chloro-4- (3-pyr: rolin-1-ylphenyl-lropionic acid in 30 ml of water is mixed until complete dissolution with a 50% aqueous solution of sodium hydroxide, and the latter is added After completion of the addition of the hydroxide solution, the reaction mixture has a pH of 12.5. The resulting solution is evaporated at a pressure of 0.8 mm Hg, and the residue after evaporation is dissolved in isopropyl alcohol. The solution is separated from the insoluble fraction and the filtrate is evaporated. The precipitate released during cooling and seeding The crystals of the obtained compound are filtered and dried for 16 hours at 90 ° C and 0.8 mm Hg. As a result of the operations, sodium a-3 chloro-4- (3-pyrrolin-1-yl) phenyl is obtained. propionic acid, T. pl. 207-210 °.

5 Example 10. A mixture containing 10.8 g of a hydrochloric acid salt of ethyl 4-aminophenylacetic acid ester, 32.4 g of 1,4-dibromo-2 butene, 84 g of sodium bicarbonate and 500 ml of dimethylformamide is boiled with stirring refrigerate for 6 hours and then the reaction mixture is filtered while hot. The filtrate is evaporated under reduced pressure. The residue after evaporation, containing 4- (pyrrolin-1-yl) phenylacetic acid ethyl ester, is treated with 150 ml of a 25% aqueous solution of sodium hydroxide and the mixture is heated under reflux for one hour. Directly

After this, the reaction mass is cooled, washed with ether and adjusted to 5 by adding hydrochloric acid, after which it is extracted with ether. The organic extract is dried, filtered

5 and evaporated. As a result of the operations, 4- (3-pyrrolin-1-yl) phenylacetic acid is obtained with a mp. 162-165 °.

If the proposed method uses the appropriate starting products,

It is then possible to obtain 4- (1,2,5,6 tetrahydropyridyl) phenylacetic acid ethyl ester with bands characteristic of IR spectroscopy at 5.86 μm and 6.08 μm, and also obtained by hydrolysis of 4- (1.2, 5,6-tetra5 hydronyridyl) acetic acid.

Subject invention

The method of obtaining a- (aminophenyl) -aliphatic carboxylic acids of general form3ly I

TO

CH-R

N

 /

I

In

13

where R is a functionally modified carboxyl group in some cases, Ri is hydrogen, a lower al. alkyl or cyclopropyl residue, R2 is hydrogen, halogen or

trifluoromethyl group.

A b

H-, V

A pyti or shchetiklenny alkeiylene amino radical, or derivatives thereof, characterized in that the compound of formula II

H

where X is an amino group, R, Ri, R2 - have the indicated meanings, are reacted with a glycol of the formula P1

BUT-A-IT

14 where A is relevant

l

group or its reactive derivative using the usual method with the subsequent selection of the target product known

techniques in the form of a free compound or a corresponding functional derivative of the racemate or an optically active measure.

Priority featured:

07/18/93 with R = carboxyl, carbomethoxy or carboethoxy, Ri = hydrogen, lower alkyl or cyclopropyl, R2 = hydrogen, halide or

20

trifluoro methyl group a.

- alkeylamino, X - amino group.

09/12/1959 with K - functional modified carboxyl group.