SU567402A3 - Method of preparation of quinoline derivatives and salts thereof - Google Patents

Description

METHOD OF OBTAINING QUINOLINE DERIVATIVES

(54) OR THEIR SALTS

The invention concerns a process for the preparation of new 1FIN-DERIVATIVES of quinoline of general formulas I, which can be used as intermediates in the synthesis of known pharmacologically

active compounds, namely esters of 6,7 - dialkoxyquinoline-carboxylic acids, as well as drugs containing these compounds. In the general formula,

significantly limits recrystallization (1.

When implementing the proposed method, new compounds of the formula I are obtained as a result of the compounds of the general formula

P

  N02

in which R and R take the above meanings for these symbols, they are subjected to reduction to a compound of the general formula

in pairs, R and R take the above-described values for these symbols, the compound obtained is reacted with dialtoxyl ether of methoxymethylene smallopic acid corresponding to the general formula

Sooya

Cshs

IV

COOR

in which R takes the values given for this symbol, and the semi-definitive compounds of the general formula

COOR

NH-CH CV

COOR2

1 13

in which R, R and R have the meanings indicated for these symbols, are introduced into the cyclisadium reaction.

In the general formula I, R is a linear or branched alkyl radical containing 1-4 carbon atoms, preferably a methyl radical.

R is a linear or branched alkyl radical containing 1-4 carbon atoms, the preferred ethyl radical and, in addition, an arylalkyl residue, preferably benzyl;

R denotes the T | hydrogen atom or lower acyl residue.

Reduction of the compounds corresponding to the general formula P is carried out mainly in the presence of a catalyst, mainly in the presence of palladium on activated carbon at atmospheric pressure or at a higher pressure.

In the reduction of acyl derivatives, the reaction is carried out predominantly in the medium of a solvent, as which it is most expedient to use ethyl acetate.

The reduction of phenols corresponding to the general formula L (R represents a hydrogen atom) is most advantageously carried out in aqueous hydrochloric acid or in a mixture consisting of an aqueous solution of hydrochloric acid and acetic acid.

The condensation reaction of the reduced compound of general formula Hi with a compound of general formula IV, in the case when R is an acyl residue, is preferably carried out in a solvent medium at

boiling point of the reaction mixture, with acetic acid ethyl ester as the solvent, for example.

If the compound of the general formula 111 is a hydroxyl compound, it is introduced into the condensation reaction with the compound of the general formula IV, also in a solvent, and the reaction is carried out with heating. As the solvent, it is most preferable to use gasoline as a diluent. Reactions also

can be melted without using a diluent.

If the reaction of the hydroxyl compound corresponding to the general formula III with the malonic acid derivative is carried out in a melt without

using a solvent, it is not necessary to isolate the compound corresponding to general formula V, and the reaction mixture is directly introduced into the cyclization reaction carried out in diphyl at a temperature of 250 ° C.

In accordance with another embodiment of the proposed method, the cyclization reaction of compounds of the general formula V, in which R represents a hydrogen atom, is carried out in

solvent medium, which is a mixture of sulfuric acid and acetic anhydride. In this case, the condensable compound is dissolved in acetic anhydride and sulfuric acid is added dropwise to the prepared solution. In the process of adding sulfuric acid dropwise, the reaction mixture is fed to approximately 60 ° C. At the indicated TeNmepaType, the reaction mixture is ground for 10 minutes. Immediately after this reaction

the mixture is poured into water, resulting in the precipitation of the product.

Example 1. 22.52 g (0.1 mol) of 4-acetoxy-3-ethoxy-nitrobenzene are dissolved in 225 ml of ethyl ester of acetic acid and in the presence of 5 g

palladium activated carbon produces hydrophobalme at a pressure of 5-Shatm. After a thorough calculation of the amount of hydrogen, the catalyst was separated by filtration, and the reaction mixture was evaporated to dryness. When cooled, the precipitated 4 acetoxy - 3 - ethoxyapilia is filtered on a suction filter, washed with cold ethyl alcohol. Yield 86%. Calculated,%: C, 61.53; H6.71; N7.17. Found,%: C 61.30; H6.40; N6.81. EXAMPLE 2 25.4 g (0.13 mol) of 4-acetoxy 3-ethoxyaniline is dissolved in 250 ml of ethyl acetate and 32.4 g (0.15 mol) of diethyl acid are added to the prepared solution. ethoxymethylenemalonic acid ester. The reaction mixture is evaporated at boiling point for 3 hours and evaporated to dryness. After cooling, the crystallized product is filtered on a suction filter, washed with cold alcohol, to obtain 91% ethyl ester of 4 - acetoxy 3 - ethoxyanilino methylenemalonic acid; m.p. 102 ° C. Calculated,%: C 59.17; H 6.54; N 3.83. Found,%: C 59.3; H 6.50; N 3.91. EXAMPLE 3 35.45 g (0.1 mol) of 4-acetoxy-3-ethoxy-1 {ylnomethylenemalonic acid Diphenor 4-acetoxy-3-ethoxy-1-acid G is heated for 60 minutes at the boiling point of the reactionone mixture in 365 ml of diphyl. The product is gradually precipitated from the solution. The suspension is cooled, diluted with 350 ml of gasoline and immediately after that filtered. The resulting product is washed on a suction filter with gasoline. As a result, with a yield of 95%, a melt is obtained at a temperature of 300 ° C with the decomposition of 6-acetoxy-7-ethoxy-4-hydroxyquinoline-3-carboxylic acid ethyl ester. After recrystallization from dimethyl sulfoxide, the melting point of the product is 310 ° C. Calculated,%: C60,18; H 5.36; N4.38. Found,%: C 60.20; H5.16; N432. Example 4. A method similar to that described above, from the ethoxymethylenemalonic acid benzyl ester instead of the ethyl ether of ethoxymethylenemalonic acid, is used to obtain the corresponding benzoyl ester compound. 4-acetoxy-3-o-octa ShIll is reacted in ethyl acetate with ethoxymethylenemalonic acid dibenzyl ester, and the obtained compound after evaporation of the reaction mixture without separating is immediately introduced into cyclization in a diphyl, to obtain 6-acetoxy-7 benzyl ester - ethoxy - 4-oxoquinoline - 3 - carboxylic acid; m.p. 260 C (with decomposition). After recrystallization from dimethyl sulfoxide, mp. 265 ° C (with decomposition). Excreted%: C 66,14; H 5.02; N 3.67. Found,%: C 65.80; H 5.27; N3.78. EXAMPLE 5. 18.31 g (0.1 mol) of 2-ethoxy-4-nitrophenol is recovered in a mixture of 180 ml of water, 10 ml of concentrated hydrochloric acid and 50 ml of acetic acid. acids, and the reaction is carried out in the presence of a catalyst, representing oo () o palladium on carbon. After separating the catalyst m filtration, the pH of the reaction mixture was adjusted to b by adding 10% sodium carbonate solution. The precipitated substance is filtered off, washed with water and then directly treated with a dry stock, to obtain 13.6 g (89%) of 2 - ethoxy - 4 am cophenol. Calculated,%: C 63.73; H 7.23; N9.14. Found,%: C62,22; H7.18; N 9.08. Example 6: 1531 g (0.1 mol) of 2 ess cc of 4 aminophenol and 26.0 g (0.12 mol) of ethoxymethylene acid ester are heated for two hours in a water bath, to the reaction mass is added 30 ml of gasoline and the mixture is heated under reflux for .2 hours. Upon cooling, a substance is removed from the two-phase mixture, which is filtered off and washed with gasoline, to obtain 27.78 g (86%) of 4-hydroxy-3-ethoxyanylnomethylenemalonic acid acid; m.p. 80 ° C. Calculated,%: C 59.43; H 6.54; N 4.33. Found,%: C 59.57; H6.61; N4.30. EXAMPLE 7 g (0.06 mol) of 4-hydroxy-3-ethoxyanilino-methylenemalonic acid ethyl ester is heated for 30 min to 190 ml of diphyl at 250 ° C, the reaction mixture is cooled and the product obtained by the cyclization reaction t in the sediment by adding 190 ml of gasoline. The product obtained is washed on the filter with gasoline; 14.8 g (89.3%) of 6-hydroxy-7-ethoxy-4-oxoquinoline-3- ethyl ester are obtained. carboxylic acid; m.p. 266 ° C. After recrystallization from dimethylformamide m.p. 270-272 ° C. Calculated,%: C 60.64; H 5.45; N 5.05. Found,%: C 60.24; H 5.55; N 5.04. EXAMPLE 8.4.59 g (0.03 mol) 2 - ethoxy - 4 minophenols and 10.52 g (0.031 mol) of ethoxymethylenemalonic acid dibenzyl ester are heated for 4 hours in a water bath at a temperature of 10 (f C , add 50 ml of diphyl and heat the mass for 60 minutes at a temperature of 250 ° C, mix with 50 ml of gasoline upon cooling, the product precipitated is filtered off and washed with alcohol; 3.4 g (50.2%) are obtained 6-hydroxy-7-ethoxy-4-oxoquinoline-3-carboxylic acid benzyl ester; mp. 25 C. Calculated,%: C67.25; H 5.05; N4.13. Found: C 66, 76; H4.88; N 4.37. PRI me R 9. A mixture consisting of The most common is 25.52 g (0.08 mol) of ethyl 6 - acetoxy - 7 ethoxy - 4 - hydroxyquinoline - 3 - carboxylic acid, 2000 ml of ethyl alcohol, 200 ml of water and g (2.4 mol) of potassium carbonate, The mixture is heated at the boiling point for 1 hour, the solvent is removed in vacuo and the resulting thick suspension is mixed with 2000 ml of water, the insoluble matter is filtered off and the product on the suction filter is suspended in 200 ml of water. The pH of the prepared suspension is adjusted to