SU1705286A1 - Method of 3-alkylsubstituted 4-hydroxyquinoline-2-ones synthesis - Google Patents

Abstract

The invention relates to derivatives of a nitrogen-containing heterocycle, in particular the preparation of 3-methyl- or 3-propyl-4-quinoline-2-one, which are used in the synthesis of biologically active substances. The goal is to increase the yield of the target product. Triethylamine and monoethyl chloroanhydride, methyl or propyl malonic acid are added to the acetone solution of ethyl anthranilate, followed by treatment of the resulting product with an aqueous solution of an alkali metal hydroxide and acidification of the reaction mixture to pH 4. These conditions ensure the yield of the desired product 92-95% against 75% in the famous case.

Description

The invention relates to organic chemistry and relates to a method for producing 3-alkyl-substituted 4-hydroxyquinolin-2-ones of the general formula I

where R is CH3 or C3H7, H being analogues of natural compounds. This method can be widely used in the synthesis of biologically active compounds in a series of quinoline derivatives.

A known method for the preparation of compound I (R — CH3) by reacting aniline with methylmalonic acid ethyl ester by heating in 53% yield (Curd FHS, Raison CG, Rose FL Synthetic antlmalarlals. Part XVII. Somearylamlnoalkylamlnoqulnollne derivatives. - J. Chem. Soc., 1947 , Ns 7.p. 899-909).

The disadvantages inherent in this method include harsh synthesis conditions (heating to 340 ° C) and the formation of symmetric dianilides, which entails a decrease in the yield of the final product and, in addition, the need for separation of by-products.

The aim of the invention is to develop a method for producing 3-alkyl-substituted 4-hydroxyquinolin-2-ones, which allows to synthesize these compounds with higher yield and a sufficient degree of purity.

The goal is achieved by the fact that these compounds are obtained by acylation of anthranilic acid esters of acid chlorides with 2-P-malonic acid monoethyl esters in an inert solvent in the presence of an acceptor

1705286 A1 of hydrogen chloride evolving, followed by treatment of the obtained products with an aqueous solution of alkali metal hydroxide and acidification of the reaction mixture to pH 4.

PRI me R 1. Z-Methyl-4-hydroxyquinolin-2-one of the formula 1.

To a solution of 8.26 g (0.05 mol) of ethylanthranilate in 20 ml of acetone was added 7.0 ml (0.05 mol) of triethylamine and dropwise 7.5 g (0.05 mol) of methyl malonic acid monoethyl ester chloride. Leave overnight at room temperature. Acetone is removed and a solution of 4.0 g (0.1 mol) of NaOH in 20 ml of water is added. Stirred for 1 h. Acidify with diluted HCI to pH 4. The precipitate formed was filtered off, washed with water, and dried. Yield 8.32 g (95%). Colorless plates with so pl. 264 ° C (ethanol).

Found. %: C 68.42; H 5.28; N, 8.04. C10H9NO2 ¹ Calculated,%: C 68.56; H 5.18; N 8.00.

PMR spectrum: 2.01 s (ZN. CH3); 7.30 m (ZN. Ar-H ^8.7.8 ); 7.97 d (1H, Ar-H ⁵ ); 10.08 s (1 N. OH); 11.32 s (1H. NH).

PRI me R 2.3-Propyl-4-hydroxyquinolin-2-one.

To a solution of 7.56 (0.05 mol) of methylanthranilate in 20 ml of methylene chloride, 4.0 ml (0.05 mol) of pyridine and dropwise 9.63 g (0.05 mol) of propylmalonic acid monoethyl ester are added dropwise. Leave for the night. The solvent was removed and a solution of 5.61 g (0.1 mol) KOH in 20 ml of water was added to the residue. Further, as in the first example. Yield 9.35 g (92%). Colorless plates with so pl. 234 ° C.

Found. %: C 71.10; H, 6.41; N, 6.96. C12H13NO2

Calculated,%; C 70.92; H 6.45; N, 6.89.

PMR spectrum: 0.90 t (ZN, CH2CH2CH3): 1.45 (2H, CH2CH2CH3); 2.54 t (2H. CH2CH2CH3): 7.31 m (ZN. Ar-H ⁶ · ⁷ · ⁸ ); 7.96 d (1H, Ar-H ⁵ ). ' 9.99 s (1H. OH); 11.26 (1H, NH). The 1 H-NMR spectra of the synthesized compounds were recorded on a Bruker WP-100 SY instrument (Germany), DMSO-O solvent, chemical shifts are given in scale d with respect to TMS.

Sample Ethyl Anthranilic Acid.

To 13.7 g (0.1 mol) of anthranilic acid, 25 ml of ethanol and 13 ml of conc. sulfuric acid. It is refluxed for 10 hours. The excess alcohol is distilled off.

The residue was cooled, 200 ml of water was added and neutralized with soda. Ethylanthranilate, isolated as a pale yellow oil, is recovered (3x40 ml) with methylene chloride. Then, the solvent is distilled off in a vacuum in a water pump. 10.9 g of ethylanthranilate are obtained, which is used in further synthesis without further purification. The aqueous layer after extraction of ethylanthranilate is acidified with HCI to pH 5-6.

2.1 g of starting anthranilic acid are isolated. which is returned to the synthesis. The yield of ethylanthranilate is 78% (based on the spent anthranilic acid).

Thus, the yield of the target 3-alkyl-substituted 4-hydroxyquinolin-2-ones of formula I, calculated on the starting anthranilic acid, by the proposed method exceeds by more than 20% the method-prototype.

Claims (1)

The claims The method of obtaining 3-alkyl-substituted 4-hydroxyquinolin-2-ones of the formula OH where R is CH3 or C3H7, by the interaction of an aromatic amine with a malonic acid derivative, characterized in that, in order to increase the yield, anthranilic acid ester is used as an aromatic amine, and malonic acid monoethyl ester of malonic acid of the formula is used as a malonic acid derivative R-CH-COOCJL · | from 3 С0С1 where R is СНЗ or С3Н7, the process is carried out in an inert organic solvent in the presence of an acceptor of hydrogen chloride, followed by treatment of the obtained products with an aqueous solution of alkali metal hydroxide and acidification to pH 4.