JP4548707B2 - Method for producing indolecarboxylic acid esters - Google Patents

Description

  The present invention relates to a method for producing indolecarboxylic acid esters useful as raw materials for pharmaceuticals, agricultural chemicals and electronic materials.

At present, indoles are widely used as raw materials for various compounds. Indole carboxylic acid esters and derivatives thereof are particularly useful as raw materials for pharmaceuticals such as antihypertensives, antidepressants, anticancer agents, and antiallergic agents, as raw materials for agricultural chemicals, and for electronic materials. Proposed. Indolecarboxylic acid esters are very useful compounds because they can be derived into any N-substituted compound.

As a known method for producing indole carboxylic acid esters, N-tosyl indole carboxylic acid esters are hydrolyzed under reflux in an alkaline aqueous solution to produce the corresponding indole carboxylic acid (Non-patent Document 1), and then indole. Although it is necessary to esterify carboxylic acids, production efficiency is very poor and there is a problem as an industrial production means. Therefore, a method for producing indolecarboxylic acid esters with high purity and industrially advantageous is desired. It was.

J. et al. Chem. Tech. Biotechnol. 36 (12), 562-564 (1986)

The present invention provides a method for producing indolecarboxylic acid esters useful as raw materials for pharmaceuticals, agricultural chemicals and electronic materials with high purity and industrially advantageously.

（Ｒ１ＯＣＯ−基は４〜7位の何れかにあり、Ｒ１は炭素数１〜４のアルキル基を表わす）で示されるインドールカルボン酸エステル類を製造するにあたり、式（２）

（Ｒ１ＯＣＯ−基は４〜７位の何れかにあり、Ｒ１は炭素数１〜４のアルキル基を表わし、Ｒ２は水素、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のハロアルキル基、炭素数２〜４のアルケニル基、ベンジル基またはフェニル基を表わす）で示されるＮ−アシルインドールカルボン酸エステル類を水および水と任意に溶解しない溶剤中で、相間移動触媒の存在下又は非存在下、塩基性物質の存在下に加水分解することより、選択的にＮ−アシル基のみが部分加水分解されて、高純度のインドールカルボン酸エステル類が工業的に有利に製造できることを見出し、本発明を完成した。 In order to solve the above-mentioned problems, the present inventors have described a method for producing indole carboxylic acid esters with high purity and industrially advantageously from N-acyl indole carboxylic acid esters. As a result of diligent investigation focusing on the method of selectively partially hydrolyzing the acyl group of the class,
Formula (1)

In the production of the indole carboxylic acid ester represented by the formula (2), the R1OCO- group is in any one of positions 4 to 7 and R1 represents an alkyl group having 1 to 4 carbon atoms.

(R1OCO-group is in any of positions 4-7, R1 represents an alkyl group having 1 to 4 carbon atoms, R2 is hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, N-acylindolecarboxylic acid ester represented by C 1-4 haloalkyl group, C 2-4 alkenyl group, benzyl group or phenyl group) in water and a solvent that does not optionally dissolve in water, By hydrolysis in the presence or absence of a phase transfer catalyst and in the presence of a basic substance, only the N-acyl group is selectively partially hydrolyzed, and high-purity indolecarboxylic acid esters are industrially produced. The present invention has been completed.

（Ｒ１ＯＣＯ−基は４〜７位の何れかにあり、Ｒ１は炭素数１〜４のアルキル基を表わし、Ｒ２は水素、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のハロアルキル基、炭素数２〜４のアルケニル基、ベンジル基またはフェニル基を表す）で示されるＮ−アシルインドールカルボン酸エステル類におけるＲ１は、炭素数１〜４のアルキル基を、Ｒ２は水素、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のハロアルキル基、炭素数２〜４のアルケニル基、ベンジル基またはフェニル基であり、Ｒ１としてはさらに具体的には例えばメチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ＣＯＲ２としてはホルミル基、アセチル基、クロロアセチル基、プロピオニル基、β−クロロプロピオニル基、ブチリル基、イソブチリル基、アクリロイル基、ベンゾイル基等が挙げられ、これらの中でもＲ１がメチル基、エチル基、ＣＯＲ２基がアセチル基、メトキシカルボニル基、エトキシカルボニル基またはベンゾイル基であることが好ましい。 Hereinafter, the present invention will be described in more detail. The N-acylindolecarboxylic acid esters in the present invention can be produced by a known method described in JP-A No. 2003-342257.
In the present invention, the formula (2)

(R1OCO-group is in any of positions 4-7, R1 represents an alkyl group having 1 to 4 carbon atoms, R2 is hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, R1 in N-acylindolecarboxylic acid esters represented by a haloalkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a benzyl group or a phenyl group) represents an alkyl group having 1 to 4 carbon atoms. , R2 is hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a benzyl group, or a phenyl group; More specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, and COR2 as formyl group, acetyl group Chloroacetyl group, propionyl group, β-chloropropionyl group, butyryl group, isobutyryl group, acryloyl group, benzoyl group, etc., among which R1 is methyl group, ethyl group, COR2 group is acetyl group, methoxycarbonyl group It is preferably an ethoxycarbonyl group or a benzoyl group.

Examples of the solvent that does not arbitrarily dissolve with water in the present invention include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene, and aliphatics such as pentane, hexane and heptane. Hydrocarbons, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, aliphatic ethers such as diethyl ether, di-n-propyl ether and methyl-t-butyl ether, methyl formate, ethyl formate, methyl acetate, Examples include esters such as ethyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate, and ketones such as methyl ethyl ketone and methyl isobutyl ketone. Among them, aromatic hydrocarbons such as toluene and xylene, chlorobenzene, dichloroethane, and methyl -T-butyl ether, ethyl acetate Preferably, furthermore toluene, aromatic hydrocarbons such as xylene are preferred.
Although the usage-amount of the solvent which does not melt | dissolve with water arbitrarily is not specifically limited, It is 2-10 weight times normally with respect to N-acyl indole carboxylic acid esters.

As the phase transfer catalyst used as necessary in the present invention, quaternary ammonium salts, quaternary phosphonium salts, crown ethers, and cryptands are used. For example, tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogensulfate, benzyltriethylammonium chloride, decyltrimethylammonium bromide, dodecyltrimethylammonium bromide, cetyltrimethyl Ammonium chloride, cetyltrimethylammonium bromide, cetyltributylammonium bromide, tetrabutylphosphonium bromide, cetyltributylphosphonium bromide, 15-crown-5, 18-crown-6, benzo-18-crown-6, dibenzo-18-crown-6 And dibenzo-24-crown-8 etc. .
The amount of the phase transfer catalyst used is not particularly limited, but is preferably 0.05 to 2 mol% with respect to the N-acylindolecarboxylic acid esters from the viewpoint of reaction rate and cost. When a phase transfer catalyst is used, the time required for the hydrolysis step can be shortened.

Basic substances used in the present invention include alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, alkyl metal carboxylates, alkali metal phosphates, alkaline earth metal Any compound of hydroxide, alkaline earth metal carbonate, alkaline earth metal carboxylate, alkaline earth metal phosphate and ammonia, or a combination of these compounds can be used.

Specific examples of the basic substance in the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, Calcium carbonate, strontium carbonate, barium carbonate, sodium bicarbonate, potassium bicarbonate, lithium acetate, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, trisodium phosphate, tripotassium phosphate, disodium hydrogen phosphate, phosphoric acid Examples include dipotassium hydrogen and ammonia. Among these, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, sodium acetate, trisodium phosphate, disodium hydrogen phosphate or ammonia, or It is preferable to use these compounds in combination.
The usage-amount of a basic substance is 1.0-4.0 times mole with respect to N-acyl indole carboxylic acid esters, Preferably it is 1.0-2.0 times mole. If the amount of alkali used is less than 1.0 mole, hydrolysis of the N-acylindolecarboxylic acid esters is not completed, and if it exceeds 4 moles, the burden of wastewater treatment increases, which is not preferable.

The reaction temperature of the present invention can be 0 ° C. or higher, but 15 to 50 ° C. is suitable for performing the reaction smoothly.

By the method of the present invention, only the N-position substituent of N-acylindolecarboxylic acid esters can be selectively hydrolyzed to obtain high purity indolecarboxylic acid esters in a high yield and industrially advantageously. it can. High-purity indole carboxylic acid esters obtained by the method of the present invention can be used as raw materials for useful indole carboxylic acid ester derivatives by introducing various substituents at the N-position.

Next, although the detail of this invention is shown in the following examples, this invention is not limited to these.

In a reaction vessel, 10 g (43.24 mmol) of ethyl N-acetylindole-5-carboxylate, 0.35 g (0.11 mmol) of tetrabutylammonium bromide, 40 g of toluene and 41.5 g (51.89 mmol) of 5% NaOH aqueous solution. ) And stirred at 30 ° C. for 2 hours. When the reaction solution was analyzed by LC, indole- 5 -carboxyethyl was 100%, and the starting material, indole-5-carboxylic acid was not present. Thereafter, the aqueous phase was separated, washed with water, and the organic layer was concentrated to obtain 8.1 g of indole-5-carboxyethyl. The yield was 99% and the purity was 99.95%.

The N-acetylindole- 5 -carboxylate of Example 1 was added to 12.7 g (43.24 mmol) of ethyl N-benzoylindole-6-carboxylate, and the basic substance was 58.2 g (51. 5%) of 5% KOH aqueous solution. 89 mmol), the same reaction and treatment were carried out to obtain 8.0 g of ethyl indole-6-carboxylate. The yield was 97% and the purity was 98.50%.

The reaction and treatment were conducted in the same manner as in Example 1 except that 0.35 g (0.11 mmol) of tetrabutylammonium bromide in Example 1 was not used and the reaction time was changed to 8 hours. Indole-5 7.7 g of ethyl carboxylate was obtained. The yield was 94% and the purity was 98.35%.

(Comparative Example 1)
The same reaction was carried out by replacing the toluene of Example 1 with ethanol. As a result of LC analysis of the reaction solution, 60% of ethyl indole-5-carboxylate and 40% of indole-5-carboxylic acid were found.

Claims (3)

Formula (1)

In the production of the indole carboxylic acid ester represented by the formula (2), the R1OCO- group is in any one of positions 4 to 7 and R1 represents an alkyl group having 1 to 4 carbon atoms.

(R1OCO-group is in any of positions 4 to 7, R1 represents an alkyl group having 1 to 4 carbon atoms, R2 is hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, N-acylindolecarboxylic acid ester represented by C 1-4 haloalkyl group, C 2-4 alkenyl group, benzyl group or phenyl group) in water and a solvent that does not optionally dissolve in water, A method for producing indole carboxylic acid esters, wherein partial hydrolysis is selectively carried out in the presence or absence of a phase transfer catalyst and in the presence of a basic substance. The method according to claim 1, wherein the solvent that does not dissolve in water is an aromatic hydrocarbon. The indole carboxylic acid ester is an indole-5-carboxylic acid alkyl (the alkyl group is methyl, ethyl, propyl, butyl), the N-acyl indole carboxylic acid ester is an N-acetyl indole carboxylic acid alkyl (the alkyl group is methyl, 3. The production method according to claim 1 or 2, which is ethyl, propyl, butyl).