SU784764A3 - Method of preparing indole derivatives or their salts - Google Patents

Description

The method consists of a denini of the general formula. . lCHj,) where R, R, R., R, A and n have the indicated values,

acylated with a compound of the general formula

Hat - CO - R

where Na is chlorine or bromine;

R „have the above values.

Compounds of formula T may be isolated from the reaction mixture and purified in the conventional manner. Such substances in the form of a free base can be converted to an acid addition salt in the usual way or vice versa.

The compounds of the formula I and their salts possess interesting pharmacological activity, especially anti-hypertensive activity, and therefore can be used as medicaments.

Example. M-Benzoyl-M (3-indolyl) -propyl -N-methyl-1,3-diaminopropane.

A solution of 10.1 g of benzoyl chloride in 15 ml of anhydrous methylene chloride is added dropwise with stirring over a period of 15 minutes, and to a solution of 14.5 g of N - 3 - (3-indolyl) -gpropyl-M-methyl-1 , 3-diaminopropane in 150 ml of anhydrous pyridine and the reddish transparent solution is stirred for 2 hours at. The resulting reaction mixture is divided into 2 and, sodium carbonate solution and methylene chloride, then the organic phase is washed, dried and evaporated. Chromatographic purification of the resinous product on alumina using methylene chloride containing 0.1–0.3% methanol gave the title compound. Naphthalene-2-sulfonate dihydrate, obtained by conventional methods after recrystallization from the methanol- (water) -ethyl acetate system (1: 1.1), has a melting point of 200 ml. 73-74 ° C.

The original compound was prepared as follows.

A. A mixture of 57 g of trifluoroacetic acid KiS1, ota and 105 g of trifluoroacetic anhydride in 400 ml of anhydrous acetonitrile is added dropwise to a stirred suspension of 95.1 g of 3- (3-indolyl) propionic acid in 500 ml of anhydrous acetonitrile and stirring continue for 30 min. With good cooling from -20 to -15 ° C, 500 ml of anhydrous pyridine is added and then 238 ml of 4.2 n solution of anhydrous methylamine in acetonitrile are quickly added. The resulting mixture is heated with stirring at 0 ° C for 15 min and maintained at for 3 hours. After the treatment, 3- (3-indolyl) -N-methylpropionamide is obtained (mp 97-98 ° C after recrystallization from the chloride system methylene-ethyl acetate).

B. A solution of 60.6 g of 3- (3-indolyl) -N-methylpropionamide in 500 ml of anhydrous tetrahydrofuran is added dropwise at 25 ° C for 15 minutes under a nitrogen atmosphere and a suspension of 34.2 g of lithium a.chuminium hydride in 300 ml of anhydrous tetraga; 1-furan and the resulting mixture is incubated for 3 hours at 66 ° C. After treatment, N-methyl-3- (3-indolyl) -propylamine is obtained (mp. 81–82 ° C after recrystallization from the methylene chloride-ethyl acetate system).

B. A mixture of 37.6 g of N-methyl-3- (3-indolyl) -propylamine and 21.2 g of acrylonitrile in 65 ml of anhydrous 1,2-dime-. xiethan, heated with stirring at 60 ° C for 2 1/2 hours. After treatment, N- (2-cyanoethyl N-methyl-3- (3-indolyl) -propylamine (m.p., 48-49 ° C) recrystallization from isopropyl ether).

G. 36.2 g of N- (2-cyanoethyl) -N-methyl-3- (3-indolyl) -propylamine is hydrogenated at normal pressure and at room temperature with 20 g of Rene nickel in 400 ml of dioxane in 400 ml of 10% ammonium solution. After treatment, (3-indolyl) -propyl N -methyl - 1, 3-diamine no-propane is obtained; m.p. neutral fumarate 180-181 ° C (decomposition). after recrystallization from ethanol.

In a similar manner, the following compounds of formula T in which X is -co-can be obtained from the corresponding compounds of formula P

The research results are presented in Table. 1 and 2.

Table

Continuation of table 1

Continuation of ta6l.1

Note.

1) Naphthalene-2-sulfonate.

2)

Kisly oxalate.

3) 4) 5)

Bis (base) -naphthalene-1,5-disulfonate,

Dihydrobromide.

Dihydrochloride 1/2 ..

6)

Primary acidic phosphate

7) 8) 9) Monohydrate.

Bis (base) sulfate; Bis (base) fumarate.

ten)

Decomposition,

Sour Lumarat

table 2

Note:

1) 2) 3)

Naphthalene-2-sulfonate

Hydrochloride

Decomposition Example 2.N-Phenylcarbamate-N-2- (3-indolyl) ethyl-d-m-methyl-1, 3-diaminopropane. 3 ml of phenyl isocyanate is added dropwise with stirring to a solution of g of (3-indolyl) -ethyl-N-methyl-1,3-diaminopropane in 25 ml of anhydrous dimethylformamide. The resulting solution was stirred for 1 h at 1015 s and evaporated. The residue is dried under high vacuum and chromatographed on silica gel with methylene chloride containing 6-10% methanol to form the compound (mp 153-155 ° C maleic acid, after decomposition after recrystallization from the alcohol-acetone system). The starting material can be obtained as follows. A. By the reaction of 3- (2-methylamino) -ethylindole with acrylonitrile in sredimethoxyethane to form H- (2-cyaioethyl) -M-methyl-2- (3-indolyl) -ethylamine, which can then be used directly. B. Reduction of N- (2-cyanoethyl) -M-methyl-2- (3-indolyl) -ethylamine on Rene nickel with the formation of N- 2- (3-indolyl) -ethyl-K-methyl-1,3-diaminopropane (t.pl. fumarata 153 154С). Example From the corresponding 3- (piperidyl-4-aminoal kil) -indoles can be obtained by a method similar to that described in Example 1, the compounds of the general formula / (CH i n -ir -CO-R i

The continuation of the table 2 of the invention for the preparation of derivatives of formula VJ (CK) - K-A-1 -CO-Kz is 1,4-cytohexylidene or trimethylamine, hydrogen or alkyl substituted by alkyl or A, together with R and a nitrogen atom, to which the radical R is bonded, form a 4-piperidyl radical} hydrogen or alkyl alkyl or dialkylamino, a phenylamino group, the phenyl ring of which may be unsubstituted or MONO-, di- or tri-substituted by halogen, alkyl C-C 4 alkoxy or dialkylamino C-C jphenyl or benzyl, the phenyl rings of which can be or mono-, di- or trisubstituted independently of one another by halogen, hydroxy, alkyl-, alkoxy- or di-lkylamino-oxy group 2, or 4-pyrindylmethyl, or ajxjMamatic 5- or 6-membered heterocycle containing one heteroatom selected from nitrogen, oxygen or sulfur, and sometimes additionally containing one or two more nitrogen atoms; hydrogen, chlorine, bromine or alkyl f — p -4-4 hydrogen, alkyl, alkoxy or alkylthio group 2 or 3,

or their salts, characterized in that the compounds of the general formula

RI i - {SKG} p-31-A-1Sh

Z4

where R.Rj ,. 4- have the indicated values acylated with a compound of the general formula

Hat -Co - R-3,

where Nar is chlorine or bromine;

R is as defined above

and the desired product is isolated in free form or in the form of salts.

Sources of information taken into account in the examination

1. Weigand-Hilgetag, Methods of experiment in organic chemistry, Chem., 1968, p. 431.

Claims (1)

SUMMARY OF THE INVENTION A method for producing derivatives of the general formula —1G (cc _x ) _p- m-A-k - co - g ₃ I I where A is 1,4-cyclohexylidene or trimethylene substituted with alkyl-C ₊ ; R.- hydrogen or alkyl C ^ -Cy or A, together with R _i and the nitrogen atom to which the radical R ₄ is bound, form a 4-piperidyl radical; Rjq hydrogen or alkyl C., - Cy; R is alkyl or dialkylamino C ^ -C ^, 'phenylamino group, the phenyl ring of which may be unsubstituted or mono-, di- or trisubstituted by halogen, C ₄ ~ C alkyl, alkoxy or dialkylamino C ₄ -C.0 phenyl or benzyl, phenyl rings of which may be unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl, alkoxy or diylalkylaminooxy group C ₄ -C ₄ ; 2, Dili 4-pyridylmethyl, or aromatic 5- or 6-membered 'heterocycle containing one heteroatom selected from nitrogen, oxygen or sulfur, and sometimes additionally containing one or two nitrogen atoms; R.- hydrogen, chlorine, bromine or alkyl Su-Sc. " Ry is hydrogen, alkyl, alkoxy or alkylthio group C ₄ -C ^; η *> 2 or 3, or salts thereof, with I 1 otlichayuschiy- in that compounds of the general formula fl -n- (CH _{z) n-e-l-tm} I n where R ^., Rj-, A and n have the above meanings acylated with a compound of the general formula On £ -Co - R-j, where Haf is chlorine or bromine; R ^ - has the above meanings, and the target product is isolated in free form or in the form of a sogl.