SU437284A1 - Method for preparing indeno-pyridine derivatives - Google Patents

Description

This invention relates to the preparation of biologically active compounds that can be used in pharmaceutical practice. Using the known reaction of alkylation of the nitrogen atom of the piperidine ring in relation to 1,3,4,9b-tetrahydro 5-methyl-indeno 1,2-c pyridine made it possible to obtain new physiologically active derivatives of indenopyridine. The proposed method for the preparation of indeno-pyridine derivatives of the general formula N-A-CO-R where R is lower alkyl; cycloalkyl, unsubstituted or monosubstituted by chlorine, bromine, fluorine, methoxy, methylthio or lower alkyl, phenyl; A is a branched or unbranched alkylene group with 1-4 carbon atoms, is that 1,3,4,9b-tetrahydro5-methylindo-1,2-c pyridine or its salt is reacted with a compound of general formula X-A- CO-R 5 10 15 20 25 30 where R and A have the indicated meanings; X is halogen, in an inert organic solvent, for example, chloroform, dimethylformamide, preferably at 50-70 ° C, in the presence of an acid acceptor, for example, an alkali metal carbonate, triethylamine, followed by isolation of the target product in a known manner. Example 1. 2-acetonyl-1,3,4, 9H-tetrahydro-5-methyl-2H-indeno 1,2-c pyridine. A mixture of 20.6 g of 1,3,4,9L-tetrahydro-5-methyl2H-indeno 1,2-c pyridine, 18.4 g of potassium carbonate and 10.7 ml of chloroacetone in 130 ml of dry chloroform is heated for 17 hours, stirring until boil. After cooling, filter the reaction mixture and wash the filtrate with water. Dry with magnesium sulfate, evaporate the solvent, and dissolve the residue in ethanol. Add the calculated amount of ethanolic hydrochloric acid and allow to crystallize. Without further purification, pure 2-acetonyl-1,3,4,9b-tetrahydro5-methyl-2H-indeno 1,2-c pyridine hydrochloride is obtained with a melting point of 214-215 ° C. Example 2. 1,3,4,9b-tetrahydro-5-methyl-2- (2-oxofenethyl) -2H-indeno 1,2-c pyridine. to a suspension of 15.8 g of 1,3,4,9btetrahydro-5-methyl-2H-indeno 1,2-c pyridine hydrochloride and 21.65 g of potassium carbonate in 60 ml of dimethylformamide, a solution of 12.2 g of phenacyl chloride in 25 ml of dimethylformamide at 70 ° C. The reaction mixture is allowed to react for one hour at 70 ° C, then it is poured into 1000 ml of water, brought to a strongly alkaline solution with dilute sodium hydroxide solution, extracted with benzene and the extracts are dried with magnesium sulfate. The remaining residue after evaporation of the solvent is dissolved in ethanol and the calculated amount of ethanolic hydrochloric acid is introduced into it. Dilute with ether until slightly cloudy and allow to slowly crystallize. A pure 1,3,4,9b-tetrahydro-5-methyl-2- (2-oxofenethyl) -2H-indeno 1,2-c pyridine hydrochloride is obtained with m.p. 202-205 ° С (decomposition). Analogously to Example 2, the following compounds are prepared: 1,3,4,9b-tetrahydro-5-methyl-2- {5-methyl 3-oxohexyl) -2H-indeno 1,2-with pyridine; m.p. hydrochloride 184-186 ° C (decomposition); 1, 3,4,9L-tetrahydro-5-methyl-2 - (3-oxobutyl) -2H-indeno 1,2-c pyridine, m.p. hydrogen fumarate 185-186 ° C when decomposed with the preceding t. pl. 144 ° C; m.p. methanesulfonate 160.5-161.5 ° C (decomposition); m.p. hydrochloride 164-166 ° C (decomposition); 1,3,4,9b - tetrahydro-5-methyl-2- (2-methyl-Zoxobutyl) -2H-nndo-1,2-c pyridine; m.p. hydrochloride 180-182 ° C (decomposition); 1,3, 4, 9b - tetrahydro-5-methyl-2- (3-oxopentyl) - 2H-indeno 1,2-c pyridine; m.p. hydrochloride 176-178 ° C (decomposition); 1,3,4,9b - tetrahydro - 5-methyl-2- (4,4-dimethyl-3-oxopentyl) -2H-indeno 1,2-c pyridine; m.p. hydrochloride 193-194 ° C (decomposition). Froze 1,3,4,9b - tetrahydro-5-methyl2- (4-methyl-3-oxopentyl) -2H-indeno 1,2-c pyridine. 18.0 g of tetrahydro-5-methyl-2H-nndeno 1,2-c pyridine hydrochloride, 18.1 g, potassium carbonate, 28.1 g and potassium iodide 1.3 g in 200 ml of dimethylformamide are added to a suspension in 2 hours to a suspension 13.2 g of 1-chloro-4-methyl-3-pentanone, stirring at 50 ° C. The reaction mixture is allowed to react for one hour at 50 ° C, then it is diluted with 500 ml of benzene. Extracted three times with water, dried the organic phase with magnesium sulfate and evaporated the solvent. The residue is dissolved in acetone and the calculated amount of ethanolic hydrochloric acid is added to it. After recrystallization of the precipitated crude crystallisate from methanol / ether, a hydrochloride of the title compound is obtained with a mp. 180-182 ° C (decomposition). Similarly to Example 3, the following compounds are also prepared: 1,3,4,9L - tetrahydro-5-methyl-2- (4-oxopentyl) -2H-indeno 1,2-c pyridine, m.p. hydrochloride 186--1-88 ° C; 2- (4-p-fluorophenyl-4-oxobutyl) -1,3,4, 9L-tetrahydro-5-methyl-2H-indeno 1,2-c pyridine; m.p. hydrochloride 227-229 ° C. Example 4. 2- (3-cyclopentyl-3-oxopropyl) - 1,3,4,9b-tetrahydro-5-methyl-2H-indeno U2-c pyridine. To a solution of 18.0 g of 1,3,4,9b tetrahydro-5-methyl-2H-indeno 1,2-c pyridine hydrochloride and 20.0 g of triethylamine in 100 ml of dimethylformamide, a solution of 19.6 g of 1-chloro-Cyclopentyl 3-propanone in 50 ml of dimethylformamide, stirring at 50 ° C. The reaction mixture is then allowed to react for another 10 minutes at the same temperature, but then it is diluted with benzene. Extract the reaction mixture 4 times with water and precipitate the organic phase with magnesium sulfate. Solvent is extracted under reduced pressure, the residue is dissolved in methanol and a calculated amount of ethanolic hydrochloric acid and ether are added to it. Recrystallize the crystallized product once more from methanol / ether; m.p. hydrochloride 196-198 ° C (decomposition). Analogously to Example 4, the following compounds were also prepared: 2- (3-cyclohexyl-3-oxopropyl) - 1,3,4,9L tetrahydro-5-methyl-2H-indeno 1,2-with pyridine; m.p. hydrochloride 194-196 ° C (decomposition); 1,3,4,9b - tetrahydro-2 -. "- methoxyphenacyl5-methyl-2P-indeno 1,2-c pyridine; so nl hydrochloride 199-202 ° C (decomposition); 2 - "- bromophenacyl - 1,3,4,9b - tetrahydro - 5methyl - 2H-indeno 1,2-c pyridine; m.p. hydrochloride 233-235 ° C (decomposition) of isopropanol / water; 2-p-chlorfenacl - 1,3,4,9b - tetrahydro - 5methyl-2H-indeno 1,2-c pyridine; m.p. hydrochloride 230-232 ° C (decomposition) of methanol; 1,3,4,9b - tetrahydro - 2-p-methoxyphenyl - 5methyl-2H-indeno 1,2-c pyridine; m.p. hydrochloride 221-223 ° C from ethanol. Example 5. 2-acetonyl-1,3,4,9b-tetrahydro-5-methyl-2H-indeno 1,2-c pyridine. A mixture of 39.8 g of 1,3,4,9b-tetrahydro-5-methyl2H-indeno 1,2-c pyridine and 10.7 ml of chloroacetone in 130 ml of dry chloroform is heated for 17 hours with stirring until boiling. The reaction solution is then concentrated and partitioned between benzene and water. The organic phase is evaporated and the residue is dissolved in ethanol. Add the calculated amount of ethanolic hydrochloric acid and the isolated hydrochloride of the title compound several times. Recrystallize from ethanol; m.p. 214-215 ° C

Subject invention

The method of obtaining derivatives of indeno-pyridine of the General formula

N-A-CO-R

where R is lower alkyl, cycloalkyl, unsubstituted or monosubstituted by a chlorine atom, bromine, fluorine, methoxy, methylthio or lower alkyl, phenyl;

L is a branched or unbranched alkylene group with 1-4 carbon atoms, characterized in that 1,3,4,9b-tetrahydro-5-methylindo 1,2-c pyridine or its

the salt is reacted with the compound of the general formula

X-A-CO-R,

where R and A have the indicated values, X is a halogen when heated in an inert organic solvent, such as chloroform, dimethylformamide, followed by isolation of the target product in a known manner.

2. The method according to claim 1, wherein

topics that the process is carried out at 50-70 ° C.

15

3. A method according to claim 1, characterized in that the process is carried out in the presence of an acid acceptor, for example an alkali metal carbonate, triethylamine.