CS270491B1 - Method of 7-ethyl-2-carboxy indole -2-yl acetic acid production - Google Patents

Abstract

7-Ethyl-2-carboxyindol-3-ylacetic acid is an important intermediate for production biologically active substances. According to the solution, this acid (formula i) is produced by 2-ethylphenylhydrazine condensed with 2-oxoglular acid or a dimethyl or ethyl ester thereof, obtained The 2-ethyl-phenylhydrazone of formula III is hydrogen chloride in alcohol, and finally the diester of formula IV thus prepared hydrolyses boiling with sodium or potassium hydroxide solution in water, alcohol, or mixtures thereof.

Description

The invention relates to a process for the preparation of 7-ethyl-2-carboxyindol-3-ylacetic acid of formula I.

[T] COOH ^^ COOH (I).

The diacid of formula 1 is a new substance and represents an important intermediate in the production of biologically active substances.

The essence of the process according to the invention is that 2-ethylphenylhydrazine is condensed with a ketone of general formula Π.

ROOC-CH ₂ -CH ₂ -C-COOR (H), in which R represents a hydrogen atom or a methyl or ethyl group, in ethanol or methanol in the temperature range of 40 ° C to the boiling point of the mixture, obtained 2-ethylphenylhydrazone of general formula III

COOR

COOR (III), in which R is as defined above, is cyclized by treatment with hydrogen chloride in methanol or ethanol at a temperature in the range of 50 ° C to the boiling point of the mixture, and the obtained 2-alkoxycarbonyl-7-ethylindol-3-ylacetic acid alkyl ester of formula IV

(IV), in which R ¹ represents a methyl or ethyl group, is hydrolysed with a boiling solution of an alkali metal hydroxide, e.g. sodium or potassium hydroxide, in water or in an alcohol, e.g. ethanol or methanol, or a mixture thereof.

In carrying out the process according to the invention, the process is preferably carried out in such a way that the hydrazone of the formula III is not isolated but is used directly crude in the next step.

The following examples illustrate, but in no way limit, the generality of the production method according to the invention.

Example 1

A) 2-Oxoglutaric acid 2-ethylphenylhydrazone (lil, R> h)

To a solution of 7.46 g (0.051 mol) of 2-oxoglutaric acid (II, R »H) in ethanol (20 ml) was added dropwise a solution of 6.9 g (0.351 mol) of 2-ethylphenylhydrazine in 8 ml of ethanol and the mixture is heated to reflux for 1 h. After cooling, the reaction mixture was allowed to crystallize at 15 ° C. The precipitated crystals are filtered off with suction

CS 27o491 B1 and washed with ethanol. 12.8 g (95%) of the compound of formula III (R-H) with a melting point of 146 DEG-15 DEG C. are obtained.

Β) Ethyl 2-ethoxycarbonyl-7-ethylindol-3-ylacetate (IV, R ¹ - C ₂ H _g )

To a stirred solution of 5.28 g (0.22 mol) of 2-ethylphenylhydrazone of formula III (R-H) in thiool (30 ml) was introduced hydrogen chloride for 30 minutes, the mixture gradually turning brown and spontaneously heating to boiling. At the same time, fine-grained ammonium chloride is excreted. The reaction mixture was then heated to reflux for 1 h, cooled and filtered. The crystals were washed with ethanol and the combined filtrates were evaporated in vacuo. The residue was partitioned between chloroform (30 ml) and water (30 ml). The organic phase is washed with water (10 ml), dried over calcium chloride and evaporated to dryness in vacuo. The residue is recrystallized from isopropyl alcohol or ethyl acetate. Yield 5.24 g (86.3%) of the diester of formula IV (R · · * - ^C 2 ^H 5 ^{P-8 10} * ⁰ "mp 91-93 ° C.

C) 7-Ethyl-2-carboxyindol-3-ylacetic acid (1)

A mixture of 22.11 g (0.17 mol) of the diesters of the formula IV (R ¹ C ₂ H _g ) ^and sodium hydroxide (7.5 g, 0.16 mol) in water (75 ml) is heated to reflux for 3 hours. the reaction mixture is filtered while hot, cooled and acidified with dilute hydrochloric acid to a pH of about 4. The precipitated product is filtered off with suction and dried at room temperature. 14.76 g (81.9%) of melting point 221 DEG-220 DEG C. are obtained with decomposition.

Example 1 and d 2

Following the procedure of Examples 1-A and 1-B, using diethyl 2-oxoglutarate (II, R - C ₂ H _g ) instead of 2-oxoglutaric acid, both reactions were carried out at 50 ° C for 4 h. wherein the compound of formula III (R - ^C ₂ ^{H 5} * ^{not of the} J l ^{u e »is} prepared diethyl ester IV (R - ^C 2 ^{H b)} νγ! ® ^ ¹⁴ 79.3%.

Example 3

Following the procedure of Example 1-C, using potassium hydroxide instead of sodium hydroxide and replacing water with ethanol or a mixture of methanol and water (1: 1), methyl 7-ethyl-2-methoxycarbonylindol-3-ylacetate (IV , R ¹ > CH 2) prepares the acid of formula I in a yield of 83.1%. The properties of the acid are identical to Example 1-C.

Example4 ·

Following the procedure of Examples 1-A and 1-B, dimethyl-2-oxoglutarate (II, R ^CH ₃ ) was used instead of 2-oxoglutaric acid and methanol was used instead of ethanol, the hydrazone of formula III (R - CH 2) ^{was used.} does not isolate, the methyl ester of formula IV (R ¹ - CH 3) is obtained in a yield of 81.2%. Melting point 133-137 ° C.

Claims (2)

OBJECT OF THE INVENTION 1. Process for the preparation of 7-ethyl-2-carboxyindol-3-ylacetic acid of formula I CS 27o491 B1, characterized in that 2-ethylphenylhydrazine is condensed with a ketone of general formula II ROOC-CH -CH--C-COOR II o (II). in which R represents a hydrogen atom or a methyl or ethyl group, in ethanol or methanol in the temperature range of 40 ° C to the boiling point of the mixture, the obtained 2-ethylphenylhydrazone of general formula III (ΙΠ), in which R is as defined above. is cyclized by the action of hydrogen chloride in methanol or ethanol at a temperature in the range of 50 ° C to the boiling point of the mixture. and the obtained 2-alkoxycarbonyl-7-ethylindol-3-ylacetic acid alkyl ester of general formula IV (IV), in which R ¹ represents a methyl or ethyl group, is hydrolysed with a boiling solution of an alkali metal hydroxide, for example sodium or potassium hydroxide, in water or in an alcohol, for example in ethanol or methanol, or in a mixture thereof. . 2. The process according to claim 1, characterized in that the 2-ethylphenylhydrazone of the formula III is used directly in the crude state in a further step.