KR100766614B1 - Method for preparing indole derivatives using decarboxylation - Google Patents

Abstract

The present invention relates to a method for preparing an indole derivative using a carboxyl leaving reaction, and more particularly, to a method for preparing an indole derivative, indole carboxylic acid derivative in a fixed bed continuous reaction system filled with a metal oxide catalyst under an inert gas atmosphere After dissolving in a solvent and injecting into the reactor, the reaction temperature is 50 ~ 500 ℃, the reaction pressure 50 ~ 2,500psig and the weight hourly space velocity (WHSV) 0.1 ~ 30h ^-1 under the reaction conditions of the process for the preparation of indole derivatives through the carboxy removal reaction It is about. The process according to the invention can provide indole derivatives in a highly productive and economical way through a relatively simple process.

Indole, carboxylic acid, leaving reaction, metal, oxide, catalyst

Description

Method for preparing indole derivatives using decarboxylation

1 is a graph showing the yield of 5-methoxy indole according to the present invention.

The present invention relates to a method for preparing an indole derivative using a carboxy derivatization reaction, and more particularly, to continuously prepare an indole derivative from an indole carboxylic acid derivative through a carboxy derivatization reaction in a fixed bed continuous reaction system filled with a metal oxide catalyst. It is about a method.

Methods for synthesizing aromatic derivatives through carboxyl leaving reactions from aromatic carboxylic acid derivatives have been disclosed in various literatures. However, the conventionally disclosed methods are not only low productivity, low yield, but also difficult to recover the catalyst used by using a batch reactor, additional processes such as neutralization and extraction process are required, and a large amount of waste is generated after the reaction. Industrial application is difficult because it is environmentally harmful.

U.S. Patent No. 5,739,388 discloses a method for preparing tetrafluorobenzene from tetrafluorobenzoic acid using a carboxyl leaving reaction using a solvent in which trialkyl amine and water are mixed at a reaction temperature of 155 DEG C under a copper oxide (1) catalyst. Is starting. However, the method according to the patent is also uneconomical, requiring various post-treatment processes such as neutralization and distillation of the reactants with an aqueous sodium hydroxide solution after completion of the reaction, followed by extraction and water removal.

U.S. Patent No. 5,872,283 discloses aromatic compounds halogenated from halogenated aromatic carboxylic acids through reaction at reaction temperatures of 80 to 180 DEG C in the presence of water and carboxyl leaving at reaction temperatures of 80 DEG C or higher in the presence of water and other acids. Disclosed is a method of preparing the same. The method according to the patent is a reaction for removing one from a compound having two intramolecular carboxylic acids, and since it uses liquid acids such as sulfuric acid and hydrochloric acid, it is environmentally harmful such as device corrosion and liquid acid treatment.

U.S. Patent No. 5,565,447 discloses 1-[[2-carboxy-3- (2-dimethylaminoethyl) -5- by carrying out a carboxylation reaction under a reaction condition of 190 DEG C using a copper oxide (1) catalyst in a quinoline solvent. 1-[[3- (2-dimethylaminoethyl) -5-indolyl] methanesulfonyl] pyrrolidine] from indolyl] methanesulfonyl] pyrrolidine] is disclosed. However, the method according to the patent is uneconomical because it requires various post-treatment processes such as adding hydrochloric acid to neutralize the reactants, removing the catalyst, and then extracting with an organic solvent after completion of the reaction.

Graham Rain. J. Org. By Graham B. Jones. Chem. 1993. Vol 58, 5558-5559, discloses a process for the preparation of indole derivatives from indole-2-carboxylic acid derivatives via carboxyl leaving reaction using quinoline as a solvent under copper chromite or copper salt catalysts. have. According to the above document, the product can be obtained in a yield of 65% when the reaction is carried out at a high temperature, but the product can be obtained in a high yield of 90% or more when the reaction is carried out in the microwave. However, all of the above production methods must undergo various post-treatment processes such as removing and extracting the catalyst using hydrochloric acid, sodium hydroxide and an organic solvent after completion of the reaction. In addition, it is difficult to apply the microwave in the industrial mass production process to improve the yield.

In order to solve the problems described above, the inventors of the present invention have repeatedly studied, in a high yield of indole derivatives from indole carboxylic acid derivatives through a simple carboxy separation process in a continuous process in a fixed bed reaction system filled with an inorganic oxide catalyst A method was found, and the present invention was completed based on this.

Accordingly, it is an object of the present invention to provide a method for producing an indole derivative which is more productive and economical in a simpler process than a conventional method through a carboxy removal reaction using a fixed bed continuous reaction system filled with an inorganic oxide catalyst.

In the method of the present invention for achieving the above object, the indole carboxylic acid derivative represented by the following formula (1) in a fixed bed continuous reaction system filled with a metal oxide catalyst in an inert gas atmosphere in a solvent in a reactor After the addition, an indole derivative represented by the following Chemical Formula 2 is obtained through a carboxyl elimination reaction under reaction conditions of a reaction temperature of 50 to 500 ° C., a reaction pressure of 50 to 2,500 psig, and a weight hourly space velocity (WHSV) of 0.1 to 30 h ⁻¹ :

In the above formula, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as or different from each other, a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or 1 to C It is an alkoxy group of 12.

Hereinafter, the present invention will be described in more detail.

As described above, the present invention relates to a method for preparing an indole derivative using a carboxyl leaving reaction, and more particularly, to a high yield of carboxy indole through an economical continuous process using a fixed bed continuous reaction system filled with an inorganic oxide catalyst. A method for preparing indole derivatives from derivatives.

The fixed bed continuous reaction system according to the present invention can obtain high productivity and yield for space time, repeatedly reuse the catalyst without additional processing, and is easy to separate the reaction product, and is also suitable for greatly simplifying the process. In the fixed bed reaction system, there is no restriction on the shape of the reactor or the direction of the input and flow of the reactants, but in order for the contact between the reactants to occur smoothly, the reactant hydrocarbons and the inert gas flow together from the top to the bottom of the reactor, and the reactants are evenly distributed throughout the reactor. It is best to use a trickle-bed reactor with dispersing equipment.

In addition, when performing the reaction, a specific solvent other than the reactant indole carboxylic acid derivative and the inert gas should be used, and the solvent serves to smoothly supply the indole carboxylic acid derivative in the solid state to the reactor. According to the present invention, the solvent does not react with the reactant indole carboxylic acid derivative and the inert gas, and a hydrocarbon capable of dissolving the indole carboxylic acid derivative and the indole derivative is preferable. Solvents usable in the present invention are polar solvents, in particular from the group consisting of ethers such as diglyme, dioxane, amines such as quinoline, and polar aprotic solvents such as dimethyl sulfoxide, dimethylformamide and dimethylacetamide You can select more than one.

The catalyst according to the present invention may be used alone or in combination with each other and inorganic oxides such as alumina, silica, silica-alumina, zirconia, titania, zinc oxide, alkali metal oxide, alkali earth metal oxide or molecular sieve, The alkali metal or alkaline earth metal may be supported and used, and the amount of the alkali metal or alkaline earth metal is preferably 50% by weight or less, more preferably 20% by weight or less based on the catalyst.

At this time, the BET surface area of the catalyst is not limited, but 10 to 1,000 m 2 / g is preferable, more preferably 20 to 500 m 2 / g, and most preferably 30 to 400 m 2 / g. The pore volume of the carrier is preferably 0.2 to 1.5 cc / g, more preferably 0.2 to 1.2 cc / g. The pore size distribution of the carrier is not limited, but the average pore diameter is preferably 500 or less as measured by the adsorption / desorption method of nitrogen.

The catalyst particles may be in the form of circular, cylindrical, granular or any type, but in order to have suitable mechanical properties, the catalyst particles are preferably molded in the form of circular or cylindrical pellets.

Through the carboxy leaving the reaction according to the invention in the manufacture of an indole derivative from indole carboxylic acid derivative, the reaction conditions are a reaction pressure of 50 ~ 2,500psig, reaction temperature 50 ~ 500 ℃ and a weight hourly space velocity (WHSV) 0.1 ~ 30h ^- It is preferable to carry out at ¹ , more preferably at a reaction pressure of 100 to 2,000 psig, a reaction temperature of 100 to 400 ° C. and a weight space velocity of 0.2 to ²⁵ h ⁻¹ , and most preferably at a reaction pressure of 100 to 1,500. psig, the reaction temperature of 100 ~ 360 ℃ and the weight hourly space velocity 1 ~ 20h ^-1 it is preferably carried out under the reaction conditions. At this time, if the reaction conditions are out of the side reaction product increases or the conversion rate is lowered.

The reaction product flowing out of the reactor may be separated by only distillation without undergoing neutralization and extraction to obtain a desired reaction product.

The present invention will be described in more detail through the following Comparative Examples and Examples, but the scope of the present invention is not limited to the following Examples.

Comparative Example 1

13.38 g (0.07 mol) of 5-methoxy indole-2-carboxylic acid, 6 g of copper chromite, and 1 liter of distilled and purified quinoline were added to a batch reactor replaced with nitrogen and reacted at a temperature of 238 ° C. I was. Samples were taken at regular time intervals and analyzed by high performance liquid chromatography to terminate the reaction when the conversion reached 99.5% and lower the reactor temperature to room temperature. The reaction cooled to room temperature was diluted with 7.5 L of ethyl acetate and washed three times with 30 L of 1% hydrochloric acid. After the acid wash was extracted twice with 7.5 L of ethyl acetate, the extract was washed twice with 7.5 L of distilled water and three times with 0.1 M aqueous sodium hydroxide solution, and then extracted twice with 7.5 L of ethyl acetate. The extract was washed with 5 L of distilled water and distilled to obtain 5-methoxy indole having a purity of 99.0%. The yield was 63%.

As described above, as a result of the experiment according to the conventional method, it is difficult to regenerate the used catalyst, undergo a complicated purification process, and have a low yield. Therefore, in order to improve the above problems, the conversion and yield of 5-methoxy indole obtained according to the following example by performing a fixed bed continuous reaction using an inorganic oxide are shown in FIG. 1 in comparison with the values of the comparative example.

Examples 1-3

The hydrated alumina was extruded into cylindrical pellets, transferred to a calcination furnace, and calcined at 550 ° C. for 6 hours to prepare a catalyst having a specific surface area of 210 m 2 / g and a pore volume of 0.60 cc / g. 5 g of the catalyst prepared according to the method were charged to a fully automated high pressure reactor made of 316 stainless steel. 100 sccm of nitrogen was flowed while raising the reactor internal temperature at a temperature increase rate of 1 ° C. per minute from room temperature to 450 ° C. After maintaining the temperature of the reactor at 450 ℃ for 3 hours, and after adjusting the reaction temperature and the reaction pressure as shown in Table 1 to maintain a constant temperature, 200 g of 5-methoxy indole-2-carboxylic acid quinoline It was dissolved in 860 g of solvent and injected into the reactor at a space velocity of 5.0 h ⁻¹ to obtain 5-methoxy indole through carboxyl leaving reaction. The conversion and selectivity of 5-methoxy indole obtained from the reaction is shown in Table 1 below.

Example Temperature (℃) Pressure (psig) % Conversion Selectivity (%) One 250 150 37.0 98.0 2 270 150 100.0 96.3 3 290 150 100.0 92.0

Examples 4-5

Silica was extruded into cylindrical pellets, transferred to a kiln, and fired at 550 ° C. for 6 hours under an air atmosphere to prepare a catalyst having a specific surface area of 380 m ² / g and a pore volume of 0.6 cc / g. 5 was obtained from the reaction after carrying out the carboxyl separation reaction according to the same method as in Example 1 except that the catalyst prepared as described above was carried out under the reaction temperature and reaction pressure shown in Table 2 below. The conversion and selectivity of methoxy indole are shown in Table 2 below.

Example Temperature (℃) Pressure (psig) % Conversion Selectivity (%) 4 280 150 76.0 98.5 5 300 150 100.0 98.0

Examples 6-7

After the carboxyl separation reaction was carried out according to the same method as Example 1 except that the silica catalyst prepared according to the method of Examples 4 to 5 and the temperature, pressure and solvent shown in Table 3 were used, The conversion and selectivity of -methoxy indole are shown in Table 3 below.

Example Temperature (℃) Pressure (psig) menstruum % Conversion Selectivity (%) 5 300 150 Quinoline 100.0 98.0 6 300 300 Diglyme 100.0 98.5 7 300 900 1,4-dioxane 100.0 98.7

The reaction product obtained in Example 6 was distilled under reduced pressure to obtain 5-methoxy indole having a purity of 99.0%, at which time the yield was 92%.

Example 8

The zirconium hydroxide was extruded into cylindrical pellets, transferred to a kiln, and fired at 500 ° C. for 6 hours under an air atmosphere to prepare a catalyst having a specific surface area of 100 m ² / g and a pore volume of 0.28 cc / g. After dissolving the catalyst prepared by the above method in a diglyme solvent and carrying out the carboxyl elimination reaction according to the same method as in Example 1 except that the reaction was carried out at the reaction temperature and the reaction pressure shown in Table 4, The conversion and selectivity of methoxy indole are shown in Table 4 below.

Example Temperature (℃) Pressure (psig) % Conversion Selectivity (%) 8 280 300 100.0 95.0

The reaction product obtained in Example 8 was distilled under reduced pressure to obtain 5-methoxy indole having a purity of 98.8%, wherein the yield was 89.0%.

Examples 9-11

Titania was extruded into cylindrical pellets, transferred to a kiln, and calcined at 500 ° C. for 6 hours to prepare a catalyst having a specific surface area of 158 m ² / g and a pore volume of 0.34 cc / g. The titania prepared according to the above method was loaded with 2% by weight of an aqueous sodium hydroxide solution or potassium hydroxide solution in the titania, respectively, and calcined at 500 ° C. for 1 hour, thereby preparing titania loaded with sodium oxide or potassium oxide. After carrying out the carboxy removal reaction according to the same method as in Example 1 except that the three catalysts prepared according to the above method were carried out in the diglyme solvent under the reaction temperature and reaction pressure shown in Table 5 below, The conversion and selectivity of 5-methoxy indole obtained from the reaction is shown in Table 5 below.

Example catalyst Temperature (℃) Pressure (psig) % Conversion Selectivity (%) 9 TiO ₂ 270 300 100.0 72.8 10 2 wt% Na ₂ O-TiO ₂ 270 300 100.0 96.7 11 2 wt% CaO-TiO ₂ 270 300 100.0 96.1

The reaction product obtained in Example 10 was distilled under reduced pressure to obtain 5-methoxy indole having a purity of 99.0%, wherein the yield was 90.3%.

As described above, the present invention provides a high-productivity, economical method for producing an indole derivative without a post-treatment process through a relatively simple carboxy separation process in a continuous process in a fixed bed reaction system filled with an inorganic oxide catalyst.

Claims (9)

In the method for producing an indole derivative, In an inert gas atmosphere, an indole carboxylic acid derivative represented by Formula 1 below was dissolved in a solvent in a fixed bed reaction system filled with a metal oxide catalyst selected from the group consisting of alumina, silica, silica-alumina, zirconia, titania, and mixtures thereof. After the addition, the reaction temperature is 50 ~ 500 ℃, the reaction pressure 50 ~ 2,500psig and the weight space velocity (WHSV) 0.1 ~ 30h ^-1 under the reaction conditions of the carboxyl leaving reaction characterized in that represented by the formula (2) Process for preparing indole derivatives: Formula 1

Formula 2

In the above formula, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as or different from each other, a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or 1 to C It is an alkoxy group of 12. [Claim ^{2] The} indole of claim 1, wherein the catalyst has a specific surface area of 10 to 1,000 m ² / g, an average pore diameter of 500 mm or less, and a total pore volume of 0.2 to 1.5 cc / g. Process for the preparation of derivatives. delete The method for preparing an indole derivative using a carboxyl leaving reaction according to claim 1, wherein an alkali metal or an alkali metal of 50 wt% or less is supported on the catalyst. The method of claim 1, wherein the reaction is a fixed bed continuous reaction. The method of claim 2, wherein the catalyst has a specific surface area of 20 to 700 m ² / g and a total pore volume of 0.2 to 1.2 cc / g. delete The method for preparing an indole derivative using a carboxyl leaving reaction according to claim 4, wherein the catalyst is loaded with an alkali metal or an alkali metal of 20% by weight or less. The method of claim 1, wherein the reaction conditions are 100 to 360 ℃ reaction temperature, the reaction pressure 100 to 1,500 psig and the hourly space velocity (WHSV) of the production of indole derivatives using a carboxy leaving reaction, characterized in that 1 ~ 20h ^-1 Way.

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