SU341231A1 - METHOD FOR OBTAINING HETEROCYCLIC CARBONIC ACIDS - Google Patents

Description

The invention relates to the field of production of heterocyclic carboxylic acids, as well as their salts.

The proposed method for the preparation of heterocyclic carboxylic acids of the formula

Zi

n soon

ji

X is an oxygen or sulfur atom;

where Y is a hydrogen atom or methyl; Zi is a fluorine or chlorine atom, methyl or

methoxy group;

Zz is a hydrogen atom or methyl and RI and R2 is methyl or ethyl is based on the hydrolysis of carboxylic acid esters known in organic synthesis.

The novel compounds have valuable pharmacological properties.

The method consists in the fact that the compound of the general structural formula

-Ch. „/) (.

- / gzh

COORj

 C

where Cs is alkyl with 1-4 carbon atoms and X, Y, Zi, Z2, RI and R2 are as defined above, hydrolyzed "isolate the desired product or convert it to salt; Rs can be methyl, ethyl, propyl, nzopropil, butyl, secondary butyl or tertiary butyl.

The hydrolysis is carried out in acidic or alkaline

medium at a temperature of 20-130 ° C, preferably at the boiling point of the solvent, in the example, in dilute hydrochloric acid or in a mixture of glacial acetic acid and concentrated hydrochloric acid. For

base or alkaline earth metal or carbonate solutions.

From solutions of alkali metal or alkaline earth metal salts of acids of formula (I), which are first obtained by hydrolysis in an alkaline medium, pure salts are isolated by concentration or evaporation and recrystallization. You can also convert the salt to acid, and then the acid again to salt.

The starting materials of formula (II) are obtained, for example, from compounds of formula (III)

where X, Y, Zi - and Zg are as defined above.

These compounds are reacted with lower alkanols, for example ethanol, in concentrated sulfuric acid to produce carboxylic esters, in particular ethyl esters. These esters are reacted with a diketone of formula (IV)

.rl2v I 2

VI

where RI and Ra are as defined above, in the presence of a base in an inert solvent, the starting materials of formula (II) are obtained.

Example 1. a) 0.8 g of 2,3-dihydro-5- (2-acetyl-3-oxo-1-butenyl) -6,7-dimethylbenzofuran-2-carboxylic acid ethyl ester is boiled for 30 minutes with reverse after stirring in a mixture of 5 ml of glacial acetic acid, 5 ml of water and 1 ml of concentrated hydrochloric acid, then the mixture is diluted with 50 ml of water, cooled and stirred for another 30 minutes.

The crude product is filtered on a suction filter, dried and recrystallized from benzene. Obtain 0.4 g of 2,3-dihydro-5- (2-acetyl-3-oxo-1-butenyl) -6,7 - dimethylbenzofuran-2carboxylic acid, so pl. 133-134 ° C; yield 55% of theoretical.

The original product, ethyl ester of 2,3-dihydro-5- (2-acetyl-3-oxo-1-butenyl) -6,7 - dimethylbenzofuran-2 - carboxylic acid, was prepared as follows:

b) 30 g of 2,3-dihydro-5-formyl-6,7-dimethylbenzofuran-2-carboxylic acid is boiled under reflux for 3 hours in 400 ml of absolute ethanol with 30 ml of concentrated sulfuric acid. Then 300 ml of ethanol are distilled off in vacuo and the residue is partitioned between 300 ml of water and 300 ml of ether. The ether phase is washed with 200 ml of water, then twice with a saturated solution of sodium bicarbonate, 100 ml each, dried over sodium sulfate and evaporated. The residue is distilled under high vacuum. Ethyl ether

2,3-dihydro-5-formyl - 6,7 - dimethylbenzofuran-2-carboxylic acid boils at 132-135 ° С (0.02 mmHg), yield 26 g (77% of the theoretical).

c) 2.0 g of ester prepared according to Example 1.6 were boiled for 2 hours in 20 ml of benzene with 0.53 g of butylamine, the water thus formed was removed by azeotropic distillation, then benzene was evaporated, the residue was dissolved in 10 ml glacial acetic acid is added

4 g of acetyl acetone a and boil a mixture of 75 L4M "under reflux, the solution is poured onto a VO ml of water and the reaction mixture is extracted with 50 ml of ether. The ether solution is washed with 50 ml of water twice with a saturated solution of sodium bicarbonate, 50 ml each time, dried over atrium sulfate and evaporated. The residue is purified by chromatography on silica gel. 0.8 g of 2,3-dihydro-5- (2-acetyl-3.-oxo-1-butenyl) -6,7-dimethylbenzofuran-2-carboxylic acid ethyl ester is obtained in the form of a colorless oil.

Example 2. a) 0.9 g of 2,3-dihydro-5- (2-acetyl-3-oxo-1-butenyl) -6-chlorobenzo-b-thiophene-2-carboxylic acid ethyl ester 30 minutes

stirring under reflux in a mixture of 5 ml of glacial acetic acid, 5 ml of water and 1 ml of concentrated hydrochloric acid. The mixture is then diluted with 50 ml of water, cooled and stirred

40 min

The crude product is filtered on a suction filter, dried and recrystallized from benzene. Obtain 0.4 g of 2,3-dihydro-5 (2-acetyl-3-oxo-1-butenyl) -6 - chlorobenzo-b | thiophene-2-carboxylic acid, so pl. 155-157 ° C; yield 50% of theoretical.

The starting material, 2,3-dihydro-5- (2-acetyl-3-oxo-1-butenyl) -6-chlorobenzo-6-thiophene-2-carboxylic acid ethyl ester, is obtained as follows:

b) 3 g of 2,3-Dygidro-5-formyl-6-chlorobenzo & -thiophene-2-carboxylic acid are refluxed for 3 hours in 40 ml of absolute ethanol with 3 ml of concentrated sulfuric acid, then in a vacuum 30 ml of ethanol are distilled off and the residue is distributed between 30 ml of water and 30 ml of ether. The ether phase is washed with 20 ml of water twice with saturated sodium bicarbonate solution.

10 ml, dried over sodium sulfate and evaporated. The residue is distilled under high vacuum. 2,3-Dihydro-5-formyl-6-chlorobenzo-b-thiophene-2-carboxylic acid ethyl ester boils at 137-145 ° С (0.02 mm Hg,

yield 24 g (70% of theoretical).

c) 2.2 g of ester prepared according to Example 2.6 were boiled for 2 hours in 20 ml of benzene with 0.53 g of butylamine, the water thus formed was removed by azeotropic distillation, added 10 ml of glacial acetic acid. are .4 g of acetylacetone and the mixture is refluxed for 75 minutes. The solution is poured onto 50 ml of water and the reaction mixture is extracted with 50 ml of ether. The ether solution is washed with 50 ml of water and twice with a saturated solution of sodium bicarbonate, 50 ml each, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel. 0.9 e of 2,3-dihydro-5- (2-acetyl-3-oxo-1-butenyl) -6-chlorobenzo- & -thiophene-2-carboxylic acid as a colorless oil.

Subject invention

The method of obtaining heterocyclic carboxylic acids of the formula I:

fft

,

CH 1

C

SOSI

where X is an oxygen or sulfur atom; Y is a hydrogen atom or methyl; Zi is a fluorine or chlorine atom, methyl or methoxy group; Zg is a hydrogen or methyl "RI and R2 is methyl or ethyl, or their salts, characterized in that the compound of formula I

j

, 7.

Rf

)

F

R7.-C

COOR-,

Ir

15

where X, Y, Zi, Za, Ri, and Rs are as defined above, and Ra is alk-yl with 1-4 carbon atoms, is hydrolyzed, and the desired product is isolated or salified using conventional techniques.

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