DE1088507B - Process for the preparation of substituted thiophene-2-carboxylic acid esters or the free carboxylic acids - Google Patents

Description

GERMAN

It has been found that substituted thiophene-2-carboxylic acid esters or the free Carboxylic acids of the general formula

Method of manufacture

of substituted
Thiophene-2-carb on acid esters
or the free carboxylic acids

R ₁ ° COOR ₄

in which R _{1 is} a low molecular weight alkyl group, R _{2 is} a hydrogen atom, a low molecular weight alkyl group or an aryl group, R _{3 is} a low molecular weight alkyl group and R _{4 is} a hydrogen atom or a low molecular weight alkyl group, if at least 2 moles of thioglycolic acid are present in the presence of an acidic condensing agent / J-diketones of the general formula

R ₂

I.

R ₁ _ CO - CH - CO - R ₃

in which R ₁ , R ₂ and R _{3 have} the meaning given, allowed to act, esterified the carboxyl groups present in the mercaptols obtained with low molecular weight aliphatic alcohols, brought about ring closure with the aid of an alkaline condensing agent and optionally saponified the esters obtained.

Up to now, thiophene carboxylic acids have only been obtained by converting other, difficult to access thiophene derivatives has been shown. In a preparative and technically useful way, they can only be removed by metalation of thiophene and its homologues and subsequent treatment with carbon dioxide or by oxidation from alkyl and acyl thiophenes. The method according to the invention enables thiophene-2-carboxylic acids and their esters in good yields by direct ring synthesis from simple, easily accessible To produce starting materials in a technically easy way.

It is known (see. Chemical reports, 89, pp. 1907 to 1912 [1956]) that the reaction of 1 mol of a / J-keto acid ester with 2 mol · thioglycolic acid available Mercaptols by a Dieckmann condensation, d. H. by an ester condensation in 3-hydroxythiophene-2-carboxylic acid ester can be transferred.

In contrast, the process according to the invention relates to a reaction of the aldol condensation type. While In the first case, 1 mole of alcohol is split off; in the second case, 1 mole of water must be used are split off, the reaction clearly initially with migration of a proton to the oxygen the carbonyl group must pass through an addition product, which then only loses water secondarily. That's why.

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning,

Frankfurt / M., Brüningstr. 45

Dr. Hans Fiesseimann, Erlangen,
has been named as the inventor

it is easily possible that the one reaction too while the other cannot be done under the same conditions. So z. B. that Addition product of acetoacetic ester with acrylic acid ester under the usual conditions for the ester condensations not cyclize (D. Vorländer, Annalen, 294, p. 316 [1897]), while the addition product of Acetoacetic ester on methyl vinyl ketone smoothly with the formation of l-methyl-cyclohexen-l-one-S-carboxylic acid- ^ ester to Ring can be closed (E. E. Blaise, Bull. Soc. Chim. France (4) 3, p. 418 [1908]).

As / S-diketones necessary for the method according to the invention are used as starting materials, for example, acetylacetone, butyrylacetone, valerylacetone, Benzoylacetone, 3-methyl-acetylacetone, 3-ethylacetylacetone, 3-butyl-acetylacetone, 3-phenyl-acetylacetone, α-acetyl-propiophenone and α-butyryl-butyrophenone in question.

The reaction according to the invention takes place over three reaction stages

R ₉ - CH- CO - R,

R ₁ -CO

R ₉ -CH-CO-R,

R ₁ -C CH ₂ -COOH

R ₂ -CH-CO-R ₃
R ₁ -C CH ₂ -COOR ₄

S-CH ₂ -COOR,

S-CH ₂ -COOH
Ro Ro

COOR ₄

009 590/410

3 4

One works in such a way that 1 mol of a / 5-Di vacuum distillation is purified; it falls as a colorless liquid

ketones with at least 2 moles of thioglycolic acid in the presence of bp ₁₂ = 115 to 119 ° C in a yield of

wait for an acidic condensing agent, preferably 61.5 g.

anhydrous hydrogen chloride, reacts. 51 g of S.S-dimethylthiophene ^ -carboxylic acid methyl ester

It is advantageous to use the. Heat of reaction through a 5 with 150 ecm of aqueous 4N potassium hydroxide solution for about 1 hour

Remove the cold bath and do not heat the temperature over to reflux; the ester goes after a short time

+ 10 ° C. Instead of anhydrous time in solution. After cooling, the solution is poured

Thioglycolic acid can also be the commercially available 80 ° / ₀ strength in a semi-concentrated hydrochloric acid to give the 3,5-di-

Acid are used. methylthiophene-2-carboxylic acid precipitates. After leaving

The mercaptols obtained in this way can immediately be sucked as raw ίο and washed with water, the product can be crystallized and esterified without further purification. The easiest way to obtain this from dilute methanol is to dissolve 41.2 g of 3,5-digelling by dissolving it in a methylthiophene-2-carboxylic acid in the form of colorless needles, low molecular weight aliphatic alcohol and melting it at 171 ° C.
Catalyst mineral acids, e.g. B. sulfuric acid, adds. It is advantageous to work at normal temperatures
temperature.

The ring closure to the thiophene-2-carboxylic acid esters 3,4,5-trimethylthiophene-2-carboxylic acid

is made by treating the esterified mercaptols with Man mixes 22.8 g of 3-methyl-acetylacetone with 36.8 g

brought about alkaline condensation agents. As anhydrous thioglycolic acid and conducts under the same

such are especially the hydroxides or 20-time cooling with an ice-table salt mixture dry

Alcoholates of the alkali metals. It is advantageous to incorporate _n en hydrogen chloride. After 20 to 25 minutes there is one

in the presence of a solvent. As such, viscous yellowish masses arose after some time

all low molecular weight aliphatic alcohols suitable. crystalline solidified.

The reaction takes place at normal or elevated temperature. The product can be removed by standing in the desiccator preferably at the boiling point of the used potassium hydroxide of adhering water and chlorine solvent, carried out. to be freed of hydrogen. By recrystallization

The thiophene-2-carboxylic acid esters are colorless liquid ethyl acetate, colorless needles are obtained

or colorless crystalline bodies that melt through.

Allow distillation or recrystallization to be easily cleaned. Dissolve 50 g mercaptole in 180 cc of 70 ° / ₀ ethyl methyl alcohol can be any one of conventional methods to give the 30 treated with 10 cc of concentrated sulfuric acid free of thiophene-2-carboxylic acids are saponified. and leaves the reaction mixture in one overnight

The products of the process are valuable intermediate separating funnels. Then you give about 500 ecm

products that can be added in various ways in pharmaceutical water and extracted with methylene chloride.

zeutica or dyes can be transferred. The methylene chloride solution is washed with bicarbonate

35 solution and water and dry them over sodium sulfate.

Example 1 After distilling off the solvent, one obtains

48.5 g of crude esterified mercaptol, which is strong as a result

3,5-Dimethylthiophene-2-carboxylic acid decomposition does not allow distillation.

In a mixture of 50 g of acetylacetone and 92 g of water-30.8 g of esterified mercaptol with 140 ecm a

Free thioglycolic acid is mixed with a 40 2N sodium methylate solution in methyl alcohol while cooling

Ice-common salt mixture, dry hydrochloric acid gas is poured in and refluxed for about 15 minutes. It is left

directs. After 15 to 20 minutes, a pale yellow appears, the reaction mixture stands for several hours and gives

very viscous liquid, which one expediently added in a finally 1.51 of water. There is an almost colour-

Pouring out porcelain bowl. After a short time it solidifies into loose precipitate. After slight acidification with

a hard crystal mass. 45 Acetic acid is suctioned off, washed with water and dried

This raw product can be used in the desiccator via sodium in the desiccator. The filtrate is shaken with methylene hydroxide dried and made of chloride for further cleaning. This can be used with after washing Ethyl acetate are recrystallized. The staining water, drying over sodium sulfate and distilling off Loose crystals melt at 93 ° C. The yield of the solvent is a further amount of the ge-130 G. 50 wanted esters to isolate. A total of 11.9 g is obtained

133.2 g of mercaptol are in 180 ecm of 80% methyl SAS-TrimethyltMophen ^ -carboxylic acid methyl ester, the alcohol dissolved. 15 ecm of concentrated sulfur is added - it can be easily recrystallized if you add it in a little acid and lets the mixture dissolve overnight in a methanol of 20 ° C and then the solution in a Separating funnel stand. The ester separates out as a yellow-ice-table salt mixture. Colorless leaves are obtained Shift off and drain. The methanolic 55 surfaces that melt at 53 ° C.

Layer is diluted with 0.51 of water and then with 9.2 g of 3,4,5-trimethylthiophene-2-carboxylic acid methyl

Shaken out methylene chloride. Esters and methylene esters are mixed in with 50 ecm aqueous 4N potassium hydroxide solution

chloride extracts are combined, heated once with bicarbonate reflux, in the course of one hour

solution and washed twice with water and passes through solution. After cooling, you pour the

Dried sodium sulfate. After distilling off the 60 solution in half-concentrated hydrochloric acid, with 8.3 g

Methylene chloride, 139 g of crude esterified acid are obtained as a flaky, colorless precipitate.

Mercaptol. The distillation under vacuum (bp. _{0, 2} = 165 ° C) Recrystallization from methanol obtained colorless

is accompanied by decomposition. Needles with a melting point of 209 ° C.

147.2 g of crude esterified mercaptol are 500 ecm

a 2N sodium methylate solution in methyl alcohol
sets and refluxed for 20 minutes. After this

Cool, mix with 1.5 liters of water and acidify 3-phenyl-5-methylthiophene-2-carboxylic acid

with glacial acetic acid. Then 32.4 g of finely powdered benzoylacetone are shaken with methylene in 36.8 g

chloride and dries over sodium sulfate. The 3,5-di anhydrous thioglycolic acid dissolved as far as possible.

methylthiophene-2-carboxylic acid methyl ester is passed into the suspension while cooling with a

Ice-table salt mixture and a strong stream of dry hydrogen chloride with the exclusion of moisture. After about 5 minutes the reaction mixture is in the form of a clear solution, after a further 20 minutes a yellow-red, viscous liquid has formed, which soon turns into a hard one Crystalline freezes.

To remove adhering hydrogen chloride and water, the product can be left in the desiccator for a few days be left over KaHumhydroxyd. By recrystallization colorless flakes with a melting point of 118 ° C. are obtained from formic acid or ethyl acetate; the yield is 64 g.

Dissolve 65.7 g mercaptole in 150 cc of 80 ° / ₀ methanol and allowing the reaction solution after addition of 15 cc of concentrated sulfuric acid, overnight in a separatory funnel stand. The esterified mercaptol is deposited as a lower, slightly yellowish layer and can be drained off. The methanolic layer is diluted with 500 ecm of water and then extracted with methylene chloride. Ester and methylene chloride are combined, washed with bicarbonate solution and water and finally dried. After the solvent has been distilled off, 66.7 g of crude product are obtained which cannot be distilled.

35.6 g of esterified mercaptol are mixed with 100 ecm of 2N sodium methylate solution in methyl alcohol. The S-phenyl-S-methylthiophene ^ -carboxylic acid methyl ester precipitates out as a colorless, coarsely crystalline precipitate with self-heating and darkening of the reaction mixture. After cooling to ⁰ ° C and neutralizing with acetic acid, filtered off with suction and washed with 80 ° / ₀ methanol. A further amount of substance can be precipitated from the filtrate by adding water. On the whole, 19.8 g of 3-phenyl-5-methylthiophene-2-carboxylic acid methyl ester are obtained, which can be purified by recrystallization from methanol; the colorless needles melt at 100 ° C.

23.2 g of S-phenyl-S-methylthiophene ^ -carboxylic acid methyl ester are poured over with 200 ecm aqueous 2 η potassium hydroxide solution and heated to reflux. After about 2 hours a clear solution has formed, which can be found after

Cool slowly poured into half-concentrated hydrochloric acid, the S-phenyl-S-methylthiophene ^ -carboxylic acid fails; the yield is 20 g. Recrystallization from dilute methanol gives the Compound in the form of colorless needles that melt at 192 ° C.

Claims (1)

PATENT CLAIM: Process for the preparation of substituted thiophene-2-carboxylic acid esters or the free carboxylic acids of the general formula R, COOR ₄ in which R _{1 is} a low molecular weight alkyl group, R _{2 is} a hydrogen atom, a low molecular weight alkyl group or an aryl group, R _{3 is} a low molecular weight alkyl group or an aryl group and R _{4 is} a hydrogen atom or a low molecular weight alkyl group, characterized in that at least 2 moles of thioglycolic acid are present an acidic condensing agent on / S-diketones of the general formula R ₁ - CO - CH - CO - R ₃ in which R ₁ , R ₂ and R _{3 have} the meaning given, allowed to act, esterified the carboxyl groups present in the mercaptols obtained with low molecular weight aliphatic alcohols, brought about ring closure with the aid of an alkaline condensing agent and optionally saponified the esters obtained. Considered publications:
Chemical Reports 89, pp. 1907 to 1912 (1956). © 009 590/410 8.60