SU457218A3 - The method of obtaining derivatives of aminoquinoline - Google Patents

Description

(54) METHOD FOR PRODUCING AMINOCHINOLIN DERIVATIVES

one

The invention relates to the field of obtaining new aminoquinoline derivatives, which can be used as therapeutic drugs. Aminoquinolines are known to be obtained by replacing chlorine in chloroquinolines with an amino group.

The proposed method for the preparation of new amipochipoline derivatives of the formula

/

С-0-СНОСНОН-СНООН

II

N o

consists in condensing a compound of the formula

COO-CH

SN-Oh.hR

 tH,

where P and Q are lower alkyl, aralkyl or aryl, with 4-chloro-7- (or 8) -trifluoromethylquinoline, in the presence of an acidic agent, which is hydrochloric or sulfuric acid, with the release of the target product or its salt by known methods.

5 The compounds obtained by the proposed method have interesting pharmacological properties, in particular, anti-inflammatory and analgesic effects. 4-chloro-7 (or 8) -trifluoromethylquinoline is obtained by cyclization in a similar way or by condensation of the corresponding substituted anilines with diethylethoxy allylacetate or ethoxymethyl diethyl malonate or p-propiolactone or acrylic acid.

5 Formed condensation products to excrete the carboxyl-containing compound are saponified, decarboxylated; then the hydroxyl in position 4 is replaced by a chlorine atom with a chlorinating agent.

0 This method of preparing 4-chloro-8-trifluoromethylquinoline has not been described in the literature and is therefore given in the experimental section. A known method for producing anthranilate 2,2-P-0-4-hydroxymethyl-1,3-dioxolane.

5 All compounds obtained by the authors are new compounds.

Example 1. 4-Chloro-8-trifluoromethylquinoline.

Stage A, o-trifluoromethylanilinomethylene diethylmalonate.

A mixture of 54.8 g of o-trifluoromethylaniline and 73.9 g of ethoxymethylene diethyl malonate is heated at 120 ° C under an inert gas atmosphere, maintained for 2 hours, and the ethanol formed is distilled off under reduced pressure. The mixture is then cooled and 115 g of o-trifluoromethylanilinomethylene diethyl malonate used in the next step are obtained.

A sample of the product obtained is recrystallized from petroleum ether. T. Kip. 65-75 ° C, so pl. 94 ° C.

Found,%: C 54; H 4.7; F 16.8; N 4.5.

C, 5H1bRzO4 (331.288).

Calculated,%: C 54.38; P 4.87; F 17.21; N 4.23.

Stage B. 3-carbethoxy-4-hydroxy-8-trifluoromethylquinoline.

The reaction mixture IZ g, obtained in stage A, with unselected o-trifluoromethylanilmethyl diethyl malonate, is quickly heated in an inert gas atmosphere. At 195 ° C, the ethanol formed begins to distil. After 30 minutes the temperature rises to about 250 ° C and then the reaction mixture is heated under reflux for 1 hour. Then the mixture is cooled, 25 ml of acetone is added, crystallized, dried; the crystals obtained are washed and evaporated to obtain 71.5 g of 3-carbethoxy-4-oxy-8-trifluoromethylquinoline with an mp. 210-214 ° C. As such, it is used in the next stage.

A sample of this product is non-recrystallized from ethanol, t. Pl. 216 ° C.

Found,%: C 54.5; H 3.8; F 19.6; N 4.9.

CisHioFsNOs (285,218).

Calculated,%: C 54.74; H 3.53; F 19.98; N 4.91.

Step B. 3-carboxy-4-hydroxy-8-trifluoromethylquinoline.

In a mixture consisting of 30 ml of water and 100 ml of Yun. 70 g of crude 3-carbethoxy-4-hydroxy-8-trifluoromethyl-quinoline obtained in Step B. The resulting reaction mixture is heated to reflux for 2 hours and 45 minutes. The resulting solution was poured into a cooled mixture of water and 100 cm of an 11.8n aqueous solution. perchloric acid.

The precipitate formed is dried, washed with water and transferred to 2 liters of 1% soda solution. The mixture is heated to 90 ° C, the resulting precipitate is filtered, the filtrate is acidified with acetic acid to pH 5.5.

The precipitate formed is evaporated and dried, yielding 58 g of 3-carboxy-4-hydroxy-8 trifluoromethylnnoline with a m.p. 290-292 ° C and used in the next stage.

A sample of the product obtained is recrystallized from acetone by heating with activated charcoal to obtain pure 3-carboxy-4-hydroxy-8-trifluoromethylquinoline with m.p. 292 ° C.

Found%: C 51.6; H 2.6; F 21.8; N 5.3. CisHeFsNOg (257,116).

Calculated%: C, 51.37; H 2.35; F 22.16; N 5.45.

This compound is not described in the literature.

Step G. 4-hydroxy-8-trifluoromethylquinoline. 56.5 g of crude 3-carboxy-4-hydroxy-8-trifluoromethylquinoline obtained in Step B are introduced into 110 ml of diphenyl ether under an inert gas atmosphere; The resulting reaction mixture is boiled under reflux for 1 hour and 50 minutes, cooled to 50 ° C, 20 ml of iso-propyl ether is added, cooled to 20 ° C and crystallized. The precipitate formed is evaporated, washed and dried, and 45.8 g of 4-hydroxy-8-trifluoromethylquinoline are obtained with a melting point of mp. 180 ° C. A sample of this product is recrystallized from acetone by heating with activated charcoal to obtain pure 4-hydroxy-8 trifluoromethylquinoline with mp. 180 ° C. Found,%: C 56.6; H 3.1; F 26.5; N 6.5.

CioHeFsNO (213,156).

Calculated,%: C 56.34; H 2.84; F 26.74; N 6.57.

Stage D. 4-Chloro-8-trifluoromethylquinoline. Phosphorus oxychloride is introduced in 130 cm of small portions of 44.3 pure 4-hydroxy-8-trifluoromethylquinoline obtained in step G; The mixture is kept at room temperature for 15 minutes, then it is refluxed for 1 hour, cooled, and the excess phosphorus oxychloride is removed by distillation under reduced pressure. Water is added to the obtained resin, cooled, and then 80 ml of an aqueous solution of ammonium hydroxide are added at 22 ° C, stirred, the aqueous layer is extracted with ether, the ether extracts are washed with a dilute aqueous solution of ammonium hydroxide and then with water.

After drying and treatment with activated carbon, the ether is evaporated to dryness, and 45.4 g of 4-chloro-8-trifluoromethylquinoline with m.p. 78 ° C, which is used to prepare pure 4- (o-methoxycarbonylphenyl) -8-trifluoromethylquinoline.

A sample of pure 4-chloro-8-trifluoromethylquinoline is crystallized from petroleum ether, i.p. 65-75 °, t. Pl. 78 ° C.

Found,%: C 52.2; H 2.3; F 24.9; C1 15.5; N 6,8.

CioHsFsCN (231,605).

Calculated,%: C, 51.86; H 2.18; F 24.61; C1 15.3; N 6.05.

Example 2. (2,3-Dioxypropyloxycarbonyl) -phenyl-amino - 8 - trifluoromethylquinoline (1).

A mixture of 48 g of anthranilate 2,2-diametyl-4-hydroxymethyl-1, 3-dioxolane (fr. Pat. No. 1421229),

42 g of 4-chloro-8-trifluoromethylquinoline (example

1), 36 ml of concentrated hydrochloric acid

and 300 ml of water, heated for 45 minutes with stirring in a flask with reflux. The mixture is filtered and the filtrate is left at 0 ° C for 3 hours. The hydrochloride that took out the hydrochloride is washed, then it is introduced into a mixture of 240 ml of dimethylformamide, 160 ml of water and 40 ml of triethylamine. The resulting precipitate is filtered, washed and dried, and 45 (2,3-dioxypropyloxycarbonyl) phenyl-amino-8-trifluoromethylquinoline is obtained with a so on. 179-180 ° C.

In the same way, starting from 4-chloro-7-trifluoromethylquinoline, (2,3-dioxypropyloxycarbonyl) -phenyl-amino-7-trifluoromethylquinoline is obtained.

Subject invention

The method of obtaining aminoquinoline derivatives of the formula

C-0-CH2SNON-SN.ON

the fact that the connection forotlichayu sh, iis mules

ten

COO-GL

Sh.Q

15

where P, Q is lower alkyl, aralkyl or aryl is reacted with 4-chloro-7 (or 8) -trifluoromethylquinoline in the presence of an acidic agent to isolate the desired product or its salt by known methods.