SU366610A1 - П / иИТНО-Т? ХНН ^ ЕСДД) а ^ - Google Patents

Description

This invention relates to methods for producing new indole derivatives that can be used in the pharmaceutical industry.

The use of a lime alkylation reaction using starting compounds containing a mobile hydrogen atom resulted in new iidol derivatives. possessing high biological activity.

The known method of obtaining

Indole derivatives of the general formula:

/ 0-CH2-CH2-N /

.

R.

f, o

one of the RI and Rz is hydrogen, chlorine, m, l, or methoxy compounds, and the other is a hydrogen atom, or both are a methylenedioxy group;

 p - alkyl, containing up to 4 carbon atoms, or together with the adjacent nitrogen atom forms a 1-pprorolidipilpuyu or piperidino group of the form ;;; / h5 - atom of hydrogen, chlorine, methyl pl. Alzoxy group, containing IA to 3 carbon atoms;

RS is alkyl, alka; 1yl, alky5 yl, containing up to 3 carbon atoms.

The proposed method consists in the fact that the metal compound of the pndol derivative of the general formula:

 iN v xO-CH7-CH2-N

25

Here, RI,, Cs, RA, or RZ, R, and RZ have 30 values stated above, borrowed from the reaction. An ester of a compound of the general formula: RQ is OH, where - has the above values, in the presence of an alkaline tinning agent, sodium sodium amide, with the following isolation of the desired product as a base or non salt into salt by the known principles. Nanrnmer dimethylformals, dimethylsulfoxide, benzene can be used as solvents. Sodium amide, lithium amide, sodium hydride or lithium hydride are most suitable as a condensing agent, under the action of which the transitional indole derivative directly B of the reaction mixture is converted into the corresponding compound containing the H1 atom of a Christmas tree.

Example 1. A solution containing 10 g (0.050 MQ.ib) 2-Be1 ZOnl-3- 2- {1-pyrrolidine) ethoxn -indole in 0 ml of phosphoric acid hexamethyltriamide was cooled in an ice bath to 10 ° and then gently mix with 6.7 ml of a 30% suspension of sodium amide in t) luol (0.050 lol). Immediately, the solution turned to an intense red color and the temperature of the re-aation mixture increased to 25 °. The solution was not placed at room temperature for another 30 minutes, then cooled again in an ice bath and added dropwise 5-10 ° 4 g (0.033 mol) of illibrmide in 10 ml of phosphoric acid hexametl triamnd in 15 min. The reaction mixture was not stirred for another 15 min at 5-lO ° and then poured into 500 ml of ice water and 250 ml of ether. The organic layer was separated, 3 times, washed with water, using 250 ml of water for each washing, and then washed over potassium carbonate. Potassium carbonate was filtered off from the dried solution and the filtrate was evaporated. The residue after evaporation, which is an oily yellow product, was dissolved in benzene, the resulting solution was filtered through 50 g of basic alumina, and the mass on the filter was then washed with 50 ml of benzene. After that, the benzene solution was evaporated. The residue after refluxing (Crude 1-alkyl-2-benzyl-3- 2- (1-pyrrolidin1yl) ethoxy-indole was dissolved in ethyl acetate and to the resulting solution was added a 6N solution of hydrogen chloride in isopropyl alcohol to acidic Congo reactions. The hydrochloric salt formed in this way was precipitated from the solution by adding ether to it, the precipitate was filtered off, the solvent was removed from it by heating in vacuum at 50 ° and then kept at room temperature until constant weight. 1 g (71% of theorine) 1-allel hydrochloric salt L2-benzoyl-3- 2- (1-pnrrolidnyl) -ethoxy-indole, which is a yellow substance with a melting point of 100-105 °.

In a similar way, from the similar penetrated indoles were obtained:

when used, 3.6 g (0.033 mol) of ethyl bromide-1-ethyl-2-beison-3- 2- (1-pyrrolidinyl) -ethoxy-indole and its hydrochloric acid salt with m.p. 107-112 °;

when used, 3.93 g (0.033 mol) of 2-propynyl-bromide-1- (2-propynyl) -2-benzoyl-3-1-1- (pyrrho- olidinyl) -ethoxy-indole and its hydrochloric acid salt with t. nl. 125 °;

Use 4.06 g (0.033 mol) of npronyl bromide - 1-propyl-2-benzoyl - 3-2-jl-pyrrolidinyl) -ethoxy-indole and its hydrochloric acid salt (dried in a high vacuum at 80 °) with m. pl. 142-143 °;

when using 4.06 g (0.033 mol) of isopropyl bromide-1 - isopropyl-2-benzoyl-3 - 2 (1-pyrrolidinyl) -ethoxy and 1 dol and its hydrochloric acid salt with m.p. 125-130 °;

with the use of 1.52 g (0.033 mol) -n-b tilbromide-1-butyl-2-benzoyl-3- 2- (1-syrrolidinyl) -ethoxy-iidol and its hydrochloric acid

salt (dried in high vacuum at 80 °)

with t. pl. 151 - 154 °.

In a similar way, in the case of use for the reaction. And other components of the al and:

starting from 10.1 g (0.030 mol) of 2-benzoyl-3 (2-diethylaminoethoxy) -indole and 3.6 g (0.033 mol) of ethyl bromide, 1-ethyl-2-benzoyl-3- (2-diethyl minoethoxy) - idol and its hydrochloric salt with m. pl. 115-120 ° (dried in high vacuum at 80 ° for 5 hours);

starting from 10.92 g (0.030 mol. mol) of 2-benzoyl-3 2- (1-pyrrolidinyl) -ethoxy-5-methoxyitdol and 3.6 g (0.033 mol) of ethylbro; mimida, 1-ethyl-2benzoyl-3 - 2- (1-pyrrolidiynol) -ethoxy-5 - methoxyindole and the hydrochloride salt of this compound with m.p. 194-197 °;

starting with 11.34 g (0.030 mol) of 2-benzo11l3- 2- (ppprrolidinyl) -ethoxy-5.6-methylenedioxyndol and 3.6 g (0.033 mol) of ethylene bromide, 1-ethnl-2-benzoyl-3- 2- (1 - pyrrolidinyl) ethoxy-5, 6-methylenedioxyindole and its hydrochloric acid salt (dried in high vacuum at 80 ° for 3 hours), with m. Pl. 188-190 °;

starting from 11.0 g of 2 - ((7-methylbenzoyl) (1-pyrrolidipyl) -ethoxy-5-methylindole; 3.93 g of allyl bromide, -1-allyl-2- (e-methyl-benzoyl) (1-pyrrolidinyl) ethoxy-5 - methylindol ii its hydrochloric acid salt with m. pl. 137- 42 °.

Example 2: 2.4 g (0.050 mol) of sodium hydride (50% suspension of 1zi in mineral oil) was suspended with a magnetic sachet in 20 ml of absolute benzene. 10 g (0.030., Go., Df) -2-benzoyl-3- 2- (1-pyrrolidinyl) ethoxy-nindola, previously dissolved in 100.; phosphoric acid hexamethyltriamide, added dropwise at room temperature and transferred to the resulting suspension for 30 minutes and the reaction mixture stirred for another 1 hour at 40-50 °. The resulting intense red colored solution of the sodium compound of the indole derivative was cooled with an ice bath and then added dropwise to the solution

stirring and 5-10 ° for 15 hours solution of 4.7 2 (0.033 mol) methyl iodide in 10 ml of phosphoric hexamethyltriamide. At the same time, the color of the reaction mass changed to yellow. After further stirring the reaction mixture for 15 minutes, while cooling with an ice bath, it was poured into 500 ml of ice water and 250 ml of diethyl ether. The organic layer was separated and washed 3 times with water, using 250 ml of water for each washing. Then the organic layer was extracted with 200 ml of 0.2N. hydrochloric acid, the acidified solution was treated with ammonia until alkaline, and the oily yellow oily substance was dissolved in 250 ml of benzene. The solution was dried over potassium carbonate and then filtered through 50 g of basic alumina. At the same time, alumina retained an ipromethylated substance. The alumina was subjected to subsequent washing with 500 ml of benzene and the combined benzene solutions were evaporated. The residue after evaporation, which is a pure 1-methyl-2-bepsoyl-3 2- (1-pyrrolidinyl) ethoxy-indole, was dissolved in 100 ml of ethyl acetate and the resulting solution was mixed with 6 g of a solution of hydrogen chloride in iso-propyl alcohol, iric the subsequent solution is added until the reaction mixture shows an acidic reaction on the congo. When shifting, crystals of hydrochloric acid salt immediately appeared. The crystalline product was filtered off and, in order to remove the solvent, was heated under vacuum, obtained with an oil pump, at 50 °. After that, the obtained product was kept at room conditions until constant weight. As a result, 9 g (75% of theory) of 1-methyl-2-beisoyl-3- 2- (1-pyrrole idinyl) -ethoxyindole were obtained as a hydrochloric acid salt with m.p. 127-129 °.

Similar methods were obtained:

when using 10.92 g (0.030 mol) of 2benzoyl-3- 2- (1-pyrrolidiyl) -ethoxy-5-methoxyindole-1 methyl-2-bepsoyl-3- 2- (1-pyrrolidiyl) -ethoxy-5-methoxyindole and salt water of this compound with m.p. 141 ° (dried in high vacuum at 80 °);

with the use of 11.34 g (0.030 mol) of 2benzoyl-2- 2- (1-pyrrolidinyl) -ethoxy-5,6-methylenedioxyindole salt of this compound with m.p. 182-185 ° (dried in high vacuum at 80 °).

In a similar manner, the following compounds were prepared:

starting from 10.44 g (0.030 mol) of 2-benzoyl-3 (2-piperidinoethoxy) -indole using 19.1 g (0.104 mol) of 1- (2-chloroethyl) -piperidine as a hydrochloric acid salt instead of 1- ( 2 chloroethyl) -1P1I1rrolidi.na as a hydrochloric acid salt, t. Pl. hydrochloric acid salt of 1- (2-chloroethyl) piperidine 226 °, received 1-methyl-2-benzoyl 3- (2-piperidinoethoxy) -indole and hydrochloric acid

salt of this compound with so pl. 140-142 ° (dried in high vacuum at 80 °);

starting from 9.24 g (0.030 mal) 2-benzoyl-3 (2-dimethyl. M | I, noethoxy) -I1I (Dola in the cl) use of 15.0 g (0.104 mol) of 2-dimethylamioethyl chloride hydrochloride in the place 1- (2-chloroethyl) -pyrrolidine hydrochloride salt, m.p. hydrochloric acid salt of 2-dimethylaminoethyl chloride 220 °, and 1-methyl-2-benzoyl-3- (2-dimethylamioethoxy) indole and the hydrochloric acid salt of this compound with m. 163-166 ° (dried for 3 hours under high vacuum at 80 °);

starting from 10.92 g (0.030 mol) of 2-benzoyl-3 (2-dipropylaminoethoxy) -iidol in case of use of 20.8 g (0.104 mol) of 2-dipropylamipoethyl chloride in the form of a hydrochloric acid salt instead of the acid salt of 1- (2- chloroethyl) -pyrrolidine, so pl. hydrochloric acid salt of 2-dipropyl. aminoethyl chloride 112-114 °, received 1-methyl-2 - benzoyl-3- (2 - dipropylaminoethoxy) indole and the hydrochloric acid salt of this compound with m.p. 172-173 ° (dried in high vacuum at 80 °);

starting from 11.72 g (0.030 mol) of 2-benzoyl3- 2- (N-methylbutylamino) -ethoxy-5.6-methylenedioxyindole as a result of the interaction of 28.1 g (0.100 mol) of 2-benzoyl-3-hydroxy-5, 6methylenedioxyindole, so pl. 125 °, and 19.4 g

(0.104 mol) of the hydrochloric acid salt of 2- (N-methylethylene butylaminio) ethyl chloride, m.p. hydrochloric acid salt 203-205 °, 1-methyl-2-benzoyl-3 2- (K1-methylenebutylamino) -ethoxy-5,6-methylenedioxyindole and the salt of this compound with fumaric acid, m.p. which is 157-159 °.

Example 3. Similar to Example 2, the following compounds were obtained from the corresponding indole derivatives:

using 11.1 g (0.030 mol) of 2- (rhlorbenzoyl) (1-pyrrolidinyl) -ethoxy indole, 1-methyl-2- (p-.orbeisoyl) (1-pyrrolidinyl) -ethoxy-indole and the hydrochloric acid salt of this compound were obtained. with t. pl. 167-169 ° (dried for 3 hours in a high vacuum npji 80 °).

When using 10.4 g (0.030 mol) of 2 (p-methylbenzoyl) -2–2- (pyrrolidmyl) ethoxy-indole, 1-methyl-2- (p-methylbeisoyl) -2–2- (1-pyrrolidnyl) - ethoxy indole and disol the acid salt of this compound with m. pl. 150-155 °;

using 11.1 g (0.030 mo, 1 2benzoyl-3-2 - (- pyrrolidiyl) - ethoxy - 6 chloroindole), 1-methyl - 2-benzoyl-3-2 (1-pyrrolidinyl) - ethoxy - 6 - chloroindole and salt were obtained an acid salt of this compound with a melting point of 138-140 °;

with the use of 11.1 g (0.030 mol) 2benzoyl - 3 - 2- (pyrrolidium1Il) - ethoxy-5 chloridol, 1-methyl-2-bizonl-3-2 (1-inrrolidinyl) - ethoxy - 5 - chloridiol and hydrochloride salt were obtained of this compound with t. nl. 207-209 °;

when using 11.4 g (0.030 needle)

2 - (p-ethoxybeisoyl) (1-pyrrolidiyl) it, xi-5-methylindole received 1.5-) Dimethyl2- (p-ethoxybenzoyl) - (bpyrrolidinyl) ethoxy-in, dol and the hydrochloric acid salt of this compound with m. : pl. 174-175 °;

using 11.2 g of 2-benzoyl-3- 2- (1-pyrrolidnyl) -etoxy-6-methoxyindole, 1-methyl-2-benzoyl-3-2- (1-pyrrolidi-nyl) -ethoxy-6-methoxyindole was obtained and the hydrochloric salt of this compound with m.p. 177-180 °.

Example 4. 14.8 g (0.035 mol of 2 - (/ 9-ethoxybenzoyl) - 3 - (2-diethylaminoethoxy) - 5.6 methylenedioxyindole) were dissolved with stirring in 100 ml of phosphoric hexamethyltriamide and the solution was cooled to 5 ° with icy ice a suspension. A suspension of 3.0 g (0.077 mol} of sodium amide in 10 ml of toluene was added to the resulting solution, the temperature of the reaction mixture increased to 15 ° C. The resulting red-colored solution was stirred eh; e 30 min at 30-35 °. Then the solution was cooled with an ice bath and a solution of 4.3 g (0.040 mol) was added dropwise to it at 15-20 ° tilbromide and 25 ml of hexamethyltriamide phosphoric acid. The color of the reaction mixture was changed from yellow to yellow. After stirring the reaction mixture for 30 minutes at 30 °, it was poured into 500 ml of ice water and 250 ml of diethyl ether. and washed 5 times with water, using 250 ml of water for each wash, then the organic phase was dried over potassium carbonate and the solvent was evaporated. The oily product left after evaporation colored in yellow was dissolved in 50 ml of benzene and the solution was filtered through 100 g of oxide a Yumin main character. In this case, alumina kept traces of the original substance. The alumina was washed with 500 ml of benzene and the combined benzene solutions were evaporated. The crude 1-ethyl-2 - (; 0-ethoxy-benzoyl) -3- (2-diethylamino-ethoxy) 5, 6-methylenedioxyindole, which remained after evaporation, was dissolved in 200 ml of ethyl acetate and 6N was added to the solution. a solution of hydrogen chloride in isopropyl alcohol to a ““ layer of reagent | ЦИ1И on Congo. The hydrochloric acid salt is crystallized by adding 100 ml of diethyl ether to the solution. The crystalline product which separated was filtered, washed with diethyl ether and dried under high vacuum at 70 °. As a result, 13.2 g of 1-ethyl-2 - ((7-ethoxybenzoyl) -3- (2-diethylaminoethoxy) -5.6 methyethylenedioxyindole were obtained in the form of a hydrochloric acid salt (77%) with a melting point. 188-190 °. In a similar way, using for the reaction, 2.12 g (0.005 mol} of the same starting material and 0.78 g of methyl iodide, 1-methyl-2 (p-ethoxybenzoyl) -3- (2-diethylaminoethoxy) 5, 6- methylenedioxindol in the form of a hydrochloric acid salt with a melting point of 145-148 ° (the free base had a melting point of 75-78 °).

Example 5. 4.22 g (0.010 mol} 2 - ((7-ethoxybenzoyl) - 3 - 2- (β-propyl-yl)) ethylKC5, 6-methylenedioxyindole) was dissolved in 50 ml of phosphoric hexamethyltriamide with stirring and the resulting solution was cooled to give using an ice bath to 5 ° C. To the cooled solution was added a suspension prepared from 900 mg (0.023 mol) of sodium salt and 3 ml of toluene. The resulting solution, painted in an intense red color, was stirred for 30 minutes at 30-35 °. Immediately after of this, the reaction solution was cooled with an ice-bath and at 10-20 ° was added dropwise to it over 10 minutes a solution of 1.32 g (0.010 mol} dimethyl sulfate in 5 ml of toluene. After stirring for another 30 minutes at 30 °, the reaction mixture was poured into 250 ml of ice water and 250 ml of diethyl ether. The resulting organic phase was separated and washed 5 times with water, using for each wash

250 ml of water. After that, the ether solution was dried over carbonic acid potassium and the solvent was evaporated. The crystalline residue with mp 97-99 ° of crude 1-methyl-2 - ((7-ethoxybenzoyl) -2-2- (1-pyrrolidinyl) ethoxn 5, 6-methyldioxyindole) was dissolved in 100 ml of ethyl acetate and the resulting solution shifted from 6 n. a solution of hydrogen chloride in isopropyl alcohol, which was added before the acidic reaction to Congo. The hydrochloric salt was crystallized by adding 20 ml of diethyl ether to the solution. The crystalline product was filtered. In order to remove the solvent, the product was heated in vacuum to 50 ° and then kept at room temperature until constant weight. As a result, 4.0 g (85% of theory) of 1-methyl-2- (p-ethoxybenzoyl) monohydrochloride (2-1 (1-1PI1rroli-1IN) -ethoxy-5,6-methyd) oxyindole with m. Pl. 148-152 °.

Subject invention

The method of obtaining derivatives of the indole formula:

.0-CHg CH2-N (

four

e is one of

hydrogen, chlorine, methyl, or methoxy, and the other is a hydrogen atom, or both are methy, lendioxy;

C and - alkyl containing up to 4 carbon atoms, or together with the adjacent nitrogen atom form a 1-pyrrolidinyl or piperidine group of the form NRzRi,

 - hydrogen atom, chlorine, methyl iLiii lower alkox group containing up to 3 carbon atoms;

 - Alkl, alkepnl, alknilyl containing up to 3 carbon atoms; or their salts,

due to the fact that the metallic compound of the idol of the general formula

where RI, Rz. RS, Cl-i, and have the above-mentioned interceptions, are subjected to a reaction with the complex ester of Compound 1 M1 with a reaction of the formula: Rg - OH, where it has the above values, in the presence of an alkaline co-bearing agent, iairi-Ler amide and sodium, followed by the selection of the target product in the form of smallpox or transfer it into salt by known lrpemp.

2. The method according to p. 1, characterized in that the process is conducted in an inert organic solvent.