SU294328A1 - - Google Patents

Description

METHOD FOR PRODUCING SUBSTITUTED p- (1-PYRRYL) PHENYL-CARBONIC ACIDS OR THEIR SALTS The invention relates to the field of producing compounds that can be used as physiologically active substances in the pharmaceutical industry. A method is proposed for the preparation of substituted (7- (1-pyrryl) -phenyl-carboxylic acids or their salts of the general formula Kc R2 I, ck-conon where RI is hydrogen, lower alkyl, alkenyl, alkynyl; Rz is hydrogen, lower alkyl, alkyloxy, halo; Кз and Rt - hydrogen or lower alkyl, by hydrolysis in basic or acidic medium of compounds of general formula RI, Ra, Кз and R4 - as indicated above, followed by separation of the target product in a known manner. Example 1. A solution of 40 g of p- (1-pyrril) ethyl acetate and 7.2 g of caustic soda in 200 L1L of a mixture of water and ethanol is refluxed for 5 hours. After evaporation in vacuo, the residue is dissolved in 400 ml of water and extracted with 100 ml of ether. The aqueous phase is separated, filtered and 5 N hydrochloric acid is added to pH 3-4. The precipitated crystals are sucked off, washed with water and dried for 14 hours at 70 ° C. Get p- (1-pyrril) phenyl-acetic acid, so pl. 180-182 ° C, which is sintered at 178 ° C. After recrystallization from a mixture of carbon tetrachloride - methanol, colorless plates are obtained, so pl. 181-182 ° C. Example 2. Prokvtiv tiv 9.1 g (0.05 mol) (1-pyrril) -phenyl-acetonitrile with a solution of 14 g (0.25 mol) of potassium hydroxide in 70 ml of methanol and 10 ml of water for 30 hours with reverse cooler, the reaction mixture is cooled, treated with water and acid. After repeated recrystallization of the residue from a mixture of carbon tetrachloride - ethyl acetate, p- (1-pyrryl) -phenyl acetic acid is obtained, so pl. 180-182 ° C.

To obtain the starting p- (1-pyrryl) -phenyl-acetonitrile, 17.8 g (0.135 mol} (p-aminophenyl) -acetonitrile and 17.8 g (0.135 mol) of 2,5-dimethoxytetrahydrofuran are boiled with 47 ml of acetic acid) acid for 2 hours under reflux. The dark reaction mixture is evaporated in a water bath (100 ° C) at 10 mm Hg 24.5 g of the partially crystallizing residue is extracted with ether for 3 hours in Soxhlet's apparatus. The resulting ether suspension is evaporated to 50 ml and cooled to -20 ° C. The crystals are separated, washed twice with ether and dried to give p- (1-pyrryl) -phenyl-acetonitrile, yellow-measles Common crystals, mp 100-102 ° C. After recrystallization from 20 ml of isopropyl alcohol and bleaching with activated carbon, a pure white substance is obtained, mp 104-105 ° C, with a positive Erlich reaction.

Example 3. 6.9 g of (1-pyrryl) -phenyl butyric acid are dissolved in 20 ml of benzene with heating and a solution of 2.7 g of 2-dimethylaminoethanol and 2 ml of benzene is added. The salt crystallizes upon grinding. It is filtered off, washed with 5 ml of cold ether and dried. After crystallization from 30 ml of benzene and drying at room temperature under high vacuum, 2-dimethylaminoethanol salt of (1-pyrryl) -phenyl-carboxylic acid is obtained, m.p. 96-100 ° C (after sintering at 91 ° C).

Example 4. 6.0 g of (-pyrryl) -phenyl butyric acid are dissolved in 10 ml of 2N KOH, filtered and evaporated in vacuo. The crystalline residue is recrystallized from a mixture of dioxane - isopropanol (10: 1), to obtain the potassium salt of (1-pyrryl) -phenyl-carboxylic acid, so pl. 255 ° C, decomposing at 230 ° C.

Example 5. To a suspension of 5.7 g of p- (1-pyrryl) -phenyl-acetic acid in 40 ml of isopropyl alcohol, 8 ml of triethylamine are added and a homogeneous solution is obtained, to which 20 ml of ether are added. After filtering and adding such a quantity of petroleum ether (m.p. 40-60 ° C) that the turbidity still disappears, the salt crystallizes gradually as it cools. T. pl. the triethylamine salt of (1-pyrril) -phenyl acetic acid, dried at 200 mmHg. Art. within 12 hours, equal to 67-73 ° C.

Example 6. 24.3 g (0.1 mol) of methyl (-pyrryl) -phenyl-butyric acid methyl ester is refluxed for 1 hour with 134 ml of 1.5N sodium hydroxide (0.2 mol) and 134 ml of ethyl alcohol. The reaction mixture is then evaporated in vacuo, the residue is dissolved in water, agitated with 100 ml of ether, filtered and acidified with 6N hydrochloric acid to pH 3-4. The precipitated crystals are separated, washed with water, dried for 15 hours at 50 ° C and 0.5 mm Hg. st., get 2- p- (1 -pyrryl) -phenyl-butyl acid, so pl. 111-112 ° C. After recrystallization from a mixture of benzene - cyclohexane (1: 1), m.p. 112-113 ° C.

Example 7. 4.20 g (0.02 mol) of (1pyrryl) -phenyl-butyronitrile are boiled with a solution of 5.61 g (0.1 mol) of potassium hydroxide in 34 ml

methanol and 6 lgl of water for 30 hours under reflux. After evaporation of the mixture in vacuo and dissolving the residue in water, the aqueous alkaline solution is shaken with ether, filtered and adjusted to pH 3-4 with 6N hydrochloric acid. The precipitated crystals are sucked off, washed with water, dried for 15 hours at 50 ° C and 6.5 mm of mercury. Art., get (1-pyrryl) -phenyl butyric acid, so pl. PO-PGS, after recrystallization from a mixture of benzene - cyclohexane (1: 1) t. Pl. 112-113 ° C.

2- p- (1-pyrril) -phenyl-butyric acid, can be obtained by hydrolysis of 4.56 g (0.02 mol) of (1-pyrryl) -phenyl-butyramide.

Preparation of raw materials 18.2 g (0.1 mol) of p- (1-pyrryl) -phenyl acetonitrile are treated with 10.9 g (0.1 mol) of ethyl bromide, as in Example 6, to obtain about 20 g of a mixture of 2- p - (1-pyrril) -phenyl-butyronitrile

and 2-ethyl-2 / 7- (1-pyrryl) -phenyl-butyronitrile, from which the pure substances are isolated by thin layer preparative chromatography. T. pl. the obtained (1-pyrril) -phenyl butyronitrile 38-39 ° C.

12.2 g (0.05 mol) of (1-pyrryl) -phenyl-butyric acid methyl ester is heated for 6 hours with 30 ml of ammonia (measured at -40 ° C) in an autoclave at 180 ° C. The reaction mixture is evaporated (at the end of the process at 50 ° C

and 0.1 mm Hg. Art.), the residue is crystallized from 60 ml of benzene. The resulting (1-pyrril) phenyl-butyramide, m.p. 141-144 ° C, dissolved for further purification in 1000 ml of ether, filtered, washed with 20 g of IN hydrochloric acid

acid and three times 50 ml of water. After the substance was taken over sodium sulfate, the ethereal solution was evaporated to 50 ml, with the formation of crystals of pure (1-pyrril) FeCl3-butyramide, m.p. 145-146 ° C.

Example 8. 4.95 g of racemic (1-pyrryl) -phenyl-butyric acid are dissolved in 30 ml of acetone and a solution of 8 g of cinchonidine in 25 ml of methanol is added, then evaporated in a water bath, 50 ml of acetone is added, again evaporated and the residue was dissolved in 50 ml of hot acetone. Upon cooling, 11 g of a mixture consisting of cinnonidine salt of (-) - 2 p- (1-pyrryl) phenylbutyric acid and a slight excess of cinchonidine are released. The salt is sucked off and recrystallized again. To do this, to 2 g of recrystallized cinchonidine salt, so pl. 140 ° C, 15 ml of 2N hydrochloric acid is added to 50 ml of water, the solution is dissolved twice with water, dried over sodium sulfate and evaporated. After recrystallization of the residue from carbon tetrachloride, (-) (1-pyrryl) -phenyl-butyric acid, m.p. 130-132С, and -39,9 °.

The stock solutions left after recrystallization of the cinchonidine salt are combined, evaporated to dryness in vacuo, the residue is suspended in 50 ml of hydrochloric acid and stirred with 50 ml of ether until all the substance has gone into solution. The ether phase is separated, washed with water, dried over sodium sulfate and evaporated. The residue (2.65 g) is dissolved in 40 ml of hot isopropanol and a hot solution of 1.8 g of (-) - a-phenylamine in 20 ml of isopropanol is added. Upon cooling, 3.2 g of the (-} -) - aphenylethylamine salt of the (- {-) (- pyrryl) -phenyl-carboxylic acid crystallizes out as colorless needles, which after two-time recrystallization from ethanol melt after the preliminary transformation at 148- 150 ° C, and -f4,4 ° (, methanol). To a suspension of 1.25 g of the obtained salt in 30 ml of water was added 10 ml of 2N hydrochloric acid and extracted with ether until complete suspension of the suspension. The ether phase is separated, washed twice with water, dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from 5 ml of carbon tetrachloride to obtain (+) (1-pyrryl) -phenyl-butyric acid, m.p. 130-132 ° С, 4-39.9 ° (с 1, methanol).

Subject invention

The method of obtaining mixed (1-pyrryl) -phenyl-carboxylic acids or their salts of the general formula

G,

RI

N -) - CH-COOH

ten

Ri is hydrogen, lower alkyl, -alkegde

Nil, alkynyl; R2 is hydrogen, lower alkyl, alkyloxy, halo;

Hz and R4 are hydrogen or lower alkyl, characterized in that the compounds of the general formula

20

where A is a cyano group, a substituted carbamoyl, a residue of a carboxylic ester or an imido ester;

RI is hydrogen, lower alkyl, alkenyl, alkynyl;

Ro is water, lower alkyl, alkyloxy, halo;

Rs and R4 are hydrogen or lower alkyl, hydrolyzed in basic or acidic medium and the desired product is isolated in a known manner.