SU385443A1 - Method of producing indol derivatives or their salts - Google Patents

Description

The invention relates to a method for producing new indole derivatives, 1 which have high physiological aktivnosti and can be used in (pharmaceutical industry. It is proposed based on the well-known reaction of alkyl alcohols of obtaining indole derivatives of the general formula where one of RI and R2 is a hydrogen atom, chlorine, methylene or methoxyl group, and the other - a hydrogen atom, or Ri and R2 together form a methylenedioxy group; Rs and R4 are alkyl, containing more than 4 carbon atoms, or (Together with the next the nitrogen atom forms a 1-lyrrolidinyl or piperidine group — NR3R4; Rs is a chlorine, hydrogen atom, a methyl or lower alcoocyl truplate containing at most 3 carbon atoms; Re is an alkyl, alkenyl, or alkynyl containing at most 3 atoms carbon, or their salts. The method consists in the interaction of the indole derivative of the general formula with the compound of the general formula Y - CH, - CH, where X "Y are atoms or atomic groups that can react with each other to form an ether bridge between position 3 of the indole and ethylene th group; Ri, R2, Rs and Re, and also Ra and R4 or -NR3R4 are as defined above. In the above formulas, X represents the atoms of hydrogen, sodium, potassium, rubidium, or trialkylammonium groups, and Y represents the atoms

halogens such as chlorine or bromine, or functionally equivalent groups, such as aromatic sulfonyl 1 x-group, similar to benzenesulfonylaxy or toluenesulfonyloxy group.

The interaction of the starting components is preferably dried in an environment of solvents such as acetone, dioxane, ethyl acetate, dimethyl sulfoxide or dimethylformamide, or in a medium that is a mixture of solvents.

In some cases, when (Conducting peaiKtion, a condensing agent is used, i.k.-quality (which can be used, for example, potassium carbonates and rubidium or sodium hydride.

Example 1. To a solution of 17.6 g (Q, Q7Q mol) of 1-methyl-2-benzoyl-3-hydroxyindole in 500 ml of ethyl acetate and 10 ml of water was added 19.0 g (0.140 mol) of potassium carbonate, and after stirring for 10 min inp commatized temperature — 12.5 g (0.0735 mol) of hydrochloric acid 1- (2-chloroethyl) -pyrrolidine salt. The reaction mixture is distilled for 15 hours under reflux — while stirring and after cooling it is washed with water (1 × 250 ml) and 1N. a solution of caustic soda (2X250 ml), and then Extracted with 0.5 n. solution of hydrochloric acid (2X250 ml). The combined acidified extracts are washed with diethyl ether, alkalinized with ammonia and the oily product which has separated out is taken up in 250 ml of benzene. After flushing with water and drying over potassium carbonate, the benzene solution is filtered through 100 g of basic alumina. Then the alumina is passed through 1000 ml of benzene, the benzene solution is evaporated, the crude 1-methyl-2-benzoyl-3- 2- (1-pyropolyidylnyl) ethyl ethoxyide, which remains after evaporation, is dissolved in 200 ml of ethyl acetate and the resulting solution is mixed with 6. N. with a solution of hydrogen chloride in isotropic alcohol to acidic reaction by koigo. The yellow crystals of hydrochloric acid salt that are separated out are filtered off, excess 1K solvent is removed by heating at 50 ° C in vacuo, and then the product is kept under room conditions to constant weight. Get 1-methyl-2-benzoyl-3- 2 - (1 - pyrroli. Dinyl) - ethoxy-indole hydrochloride, t. Pl. 127-129 ° C. The product yield of 18.1 g (64% of teorpp).

The starting 1-methyl-2-benzoyl-2-hydroxyidol is prepared as follows.

7.0 g (0.042 mol) of the methyl ester of N-methylanthranoic acid are mixed with 4.0 g (0.020 mol) of feiacyl bromide and the resulting solution is mixed with a magnetic blender. After 48 hours, the paste, which is only stirred up with difficulty, is dissolved in 100 ml of methyl alcohol, the solution is boiled in the opposite direction, and a refrigerator is poured in. For 1K, it is sodium methyl acetate solution prepared by dissolving 920 mg of sodium in 50 ml of methyl alcohol. The reaction solution was colored red intensively (boil for another 10 minutes under reflux and then evaporate the solvent in a vacuum. The residue obtained after evaporation is dissolved in 100 ml of water and washed with diethyl ether (3x50 ml) to remove the neutral part. Aqueous the red color is mixed with 12N hydrochloric acid solution until acidic in Congo. The precipitated product is filtered off with suction and washed with water until neutral reaction of the WATER wash. After drying over phosphorus pentoxide and carried out For this 1 crystallization from 300 ml of hexane, 3.2 g (64% of theory) of 1-methyl-2-: beisoyl-3-hydroxyidol are obtained, mp 110-113 ° C.

Example 2. To a solution of 3.4 g (0.010 mol) of 1-methyl-2- (p-ethaxibenzoyl) -3-hydroxy-5.6 methyldiocoinndole in 100 ml of ethyl lysrate, add with a magnetic stirrer and at room temperature 2.76 g ( 0.20 mol) potassium carbonate, and then 3 ml of water. After 10 minutes, 1.9 g (0.011 mol) of the hydrochloric acid salt of 2-diethylaminioethyl 1 chloride was added to the mixture, followed by refluxing for 10 hours. The ethyl acetate solution cooled to room temperature was first extracted with 1N. a solution of e, sodium hydroxide to remove traces of the starting compound ((SCCOO ml) and then with 1N hydrochloric acid solution (3X100 ml). The combined acidic extracts are alkalinized with ammonia. 100 ml of benzene is recovered, the benzene solution is separated and dried over potassium carbonate. After evaporation of benzene, 3.9 g (89% of theory) of 1-cmethyl-2 - (/ g-ethoxybenoyl) 3- (2-diethyl-1-amino-oxy-oxy) -5,6-methylenedioxyindole, t. 75-78 ° C. The isolated free base is converted to IB hydrochloric acid salt, and the salt is obtained after drying — you — dough under room conditions to constant weight. My l-methyl2- (d-ethol 1s-benzoyl) -3- (| 2- | Diethyl1-MINoethoxy) 5,6-methylenedioxyindole, mp 146-148 ° C is obtained.

Analogously, 1-ethyl-2- (g-ethoxybenzoyl) -3- (2-diethylaminoethoxy) -5.6-methyliedioxyindole (m.p. 188-190 ° С) salt of 1-methyl-1 2 - (p-it.xy | benzyl) (l-pypo-Lidinyl) -ethoxy-5,6-methylenedioxy-indole, t. 1PL. 148-152 ° C.

The 1-methyl-2- (p-ethoxybenzoyl) -3-hydroxy-5,6methylenedioxyindole used as the starting material and the corresponding compound substituted in position 1 with ethyl is obtained by the following o-braz.

A solution of 2.8 g (0.013 mol) of M-methyl-4,5-methylenedioxianthranilic acid ethyl ester in 3 ml of diethylene glycol dimethyl ether is mixed at 30–40 ° C with 1.4 g (0.006 mol) / 1 - ethoxyfeiatsilbromida. The resulting solution, which is a thick liquid, is moved 60 hours at

30-40 ° C with a magnetic stirrer, after which the mixture is dissolved in 20 ml of absolute alcohol, the solution is refluxed and then mixed with sodium ethoxide solution, (Prepared by dissolving 276 mg (0.012 mol) of sodium in 10 ml absolute ethyl 1C1 alcohol. The resulting solution is intensely red in color and 10 minutes under reflux and then poured in a hot state into 200 ml of ice (WATER. The insoluble part of the reaction mixture is separated by diethyl ether (2X100 ml). Then the alkaline solution is red This color is acidified with 2N hydrochloric acid TICOPOM. The yellow-brown color of the precipitated product is filtered off with suction and washed with water. After crystallization from 100 ml of ethyl alcohol, 1.35 g are obtained (70% of theory (1-meth1Il -2 (p-ethacoibenzoyl) -3-hydroxy - 5,6-methylenediaxyindole in the form of yellow crystals, mp 136-140 ° C.

Similarly, using 3.0 g (0.012 mol) of N-ethyl-4,5-methylenedioxyanthranilic acid ethyl ester, 1-e11HL-2- (n-ethoxybenzoyl) -3-hydroxy-5,6 methylenedioxyindole is obtained, t., Pl. 117-121 ° C.

Subject invention

Method for the production of aqueous indoles of the general formula

p-CHf-CH2--

at. c

where one ns RI and R2 is a hydrogen atom, a chlorine, metpl or metotshsyl group, and the other is a hydrogen atom, or R n R2 together form a methylenedioxy group;

From and R4 is alkyl, containing at most 4 ato: Ma carbon, “whether together with the adjacent nitrogen atom they form 1-pyrrolidinyl or P1Iper | I. single group NR3R4;

Rs is an atom of hydrogen, chlorine, methyl or lower alkoxyl, containing at least 3 carbon atoms;

iRe-alkyl, alkyl or alkyl, containing more than 3 carbon atoms or their salts, characterized in that it is an idole derivative of the general formula

0-x

R.

I rf

subjected to interaction with the compound of the General formula

Rs

/

Y - CH, - CH, - N R

where X and Y are atoms or atomic groups that can react with each other to form the ether bridge between Il and 3 of the indole and the ethylene cell;

Rb R2, Rs, and Re, and also Rs and R4 or -NR3R4 are as defined above, followed by isolating the desired product as a base or salting it with known techniques.