KR900007418B1 - Process for preparing indoles - Google Patents

Abstract

A process for preparing indoles of formula (III) comprises reacting glyoxal with aniline or its nuclear-substd. deriv. of formula (I) (mol. ratio of 0.5-20:1) at 15-150 deg.c to produce a cop. of formula (II), and heat-decomposing the cpd. of (II) in the presence (or absence) of a catalyst. In the formulas, X is C1-4 alkyl, nitro, OH or halogen; n is 0-4. The indoles are used as an intermediat of dyes, medicines and perfumes.

Description

Production method of indole

The present invention relates to a process for producing indoles, and more particularly to a process for producing high purity indole at low temperature without a catalyst using glyoxal.

In general, indole and its nuclear substituted derivatives are not only widely used in dye intermediates, pharmaceutical intermediates and fragrances, but also as raw materials for synthesizing dyes and alkaloids, and also as reagents for detecting nitrite ions. Since their structure determination and synthesis have a great influence on the field of organic chemistry, the research on the synthesis of indole and its nuclear substituted derivatives has been actively conducted in recent years.

Therefore, in order to synthesize indole and its nuclear substituted derivatives, the Fischer indole synthesis method in which phenylhydrazine and aldehyde are reacted is widely used. The reaction of chenylhydridine and acetaldehyde did not proceed smoothly, so that indole and its derivatives were not well synthesized. Also, US Pat. No. 2,409,676 discloses aniline (aniline) and ethanol tetrachloride to react. Synthesis of di-imine and pyrolysis to prepare indole and derivatives thereof, but in this case, there is a problem in the synthesis method such that by-products such as hydrochloric acid are produced together with indole and its derivatives. there was.

As another method, o-ethylaniline and chloroacetonitrile are reacted in the presence of 3-bromide and then reduced with sodium borohydride (NaBH ₄ ) or the like. J.MED CHEM. However, in this case, since the catalysts used during the synthesis reaction are very expensive in this case, there is a problem that the above production method is almost impossible to use industrially in terms of economy.

In addition, Japanese Patent Laid-Open No. 73-76864 discloses that in order to compensate for the above-mentioned disadvantages of the Fischer indole synthesis method, for example, phenylhydrazine and acetaldehyde are contacted with an alumina catalyst at a high temperature of 300 to 4001 ° C. to perform the synthesis reaction. In addition, in this method, the indole to be produced is easily produced, but the reaction temperature is so high that it is difficult to continue the activity of the alumina catalyst for more than 1 hour, there was a problem that the recovery rate of the indole is considerably low.

Therefore, recently, to prepare indole and its derivatives, o-methyl-N-formylaniline is prepared by mixing o-toluidine and formic acid, and then phosphorus obtained by forming a ring with potassium hydroxide (KOH) is used. In this case, however, it is difficult to selectively prepare o-toluidine, and thus it is difficult to synthesize o-methyl-N-formylaniline, which is the main raw material of indole, with high purity, and to deal with the alkalizing reaction with potassium hydroxide. There was a very uncomfortable problem.

In addition, in addition to the above-mentioned method, a method of forming indole with N-β-hydroxyethylamine under an alumina silicate catalyst at 300 ° C. has been introduced. However, in this case, the yield of indole produced is extremely low and is not widely used. to be.

Accordingly, the present invention provides a method for preparing indoles having a high yield even at low temperature without the use of expensive catalysts, by-products of impurities, and by-products of impurities are not produced. There is a purpose.

The present invention will be described in detail as follows.

In the present invention, in preparing an indole and its nuclear substituted derivative, glyoxal is added to the following general formula (I) of the aniline and its nuclear substituted derivative, and the reaction molar ratio is 0.5 to 20: 1, Synthetic reaction with or without solvent to prepare compound of formula (II) at low temperature, and indole to produce compound of formula (III) by pyrolysis under no catalyst or using metal salt as catalyst It is a manufacturing method of.

(Where X is an alkyl group having 1 to 4 carbon atoms, a nitro group, a hydroxyl group or a halogen group, n is an integer of 0 to 4, and when n≥, X may include at least two or more functional groups)

Hereinafter, the present invention will be described in more detail. In the present invention, when a primary or secondary amine compound is reacted with a ketone group of an aldehyde as in the following Reaction Formula (1), a carbinol amine compound is formed as shown in the following Formula (IV), and the compound is spontaneously formed by heat treatment. Dehydration process occurs by using the principle of forming the amine compound (V).

In this case, as primary or secondary amine compounds, aniline, 2-methyl aniline, 3-methylaniline, 4-methylaniline, 2-ethylaniline, 3-ethylaniline, 4-ethylaniline, 2-propylaniline, 3-propyl Aniline, 4-propylaniline, 2-nitroaniline, 3-nitroaniline, 4-nitroaniline, 2-aniline chloride, 2-methyl-3-nitroaniline, 2-methyl-4-nitroaniline, etc. Aniline represented by the general formula (I) and a nuclear substituted derivative thereof, and glyoxal containing an aldehyde group were used as the material to be added to the aniline and its nuclear substituted derivative.

On the other hand, the half agitation ratio of the aniline of the general formula (I), its nucleosubstituted derivatives and glyoxal is 2 molecules of the compound of the general formula (I) relative to one molecule of glyoxal as shown in the above reaction formula (2). Although the reaction rate is preferably added, the reaction rate may be changed depending on the reaction conditions. If the amount of glyoxal added is less than the reaction amount of aniline and its derivatives, glyoxal and U. The reacted aniline and its derivatives are present so as to precipitate with the compound of formula (III) upon thermal decomposition.

However, this will be clear later, but it is not a big problem in the present invention.

Here, there are various methods for adding glyoxal to the aniline and its derivatives of general formula (I), but in general, glyoxal is polymerized in an aqueous solution state, but in the present invention, glyoxal in an aqueous solution state is not used as it is. The aqueous solution in which glyoxal was polymerized was evaporated and then heated to decompose to glyoxal, and then solidified to prepare a powder, which was then introduced into the aniline and its derivatives.

As another method other than the above, glyoxal may be added directly into a container containing aniline of Formula (I) or a derivative thereof in a gaseous state, and added in a liquid state at a melting point of glyoxal of 15 ° C or higher. However, it is most preferable to add glyoxal in a liquid state at a reaction temperature of 20 to 50 ° C.

In this way, when aniline of the general formula (I) and its nuclear substituted derivative and glyoxal are reacted to obtain a diimine compound such as the general formula (II), the diimine compound undergoes a pyrolysis process. The process may be carried out simply by heating, but when the inorganic catalyst is added thereto and heated, a more effective pyrolysis process is performed.

For example, a metal salt of group IIa of the periodic table is preferable as the inorganic catalyst, and halide, sulfide, sulfenate, carbonate, nitrate, sulfate, pyrophosphate, silicate and organic acid salt may be used as the salt.

More specifically, for example, magnesium halides such as beryllium sulfate, beryllium chloride, beryllium bromide, beryllium fluoride, magnesium sulfate and magnesium chloride, magnesium phosphate, calcium sulfate, calcium halide, strontium salt and barium salt All may be used as catalysts, and other inorganic materials may be used as catalysts. The amount of catalyst added at this time is most preferably 0.1 to 2 g per mole of the diimine compound of the general formula (II).

On the other hand, the inorganic catalyst as described above may be introduced into the pyrolysis process in the form of powder, granules or lumps, and may be used as other forms, and on the other hand, the catalyst may be used as a carrier. It can also be used to support the carrier used at this time may be mainly used alumina, silica, magnesia, activated carbon, activated earth and asbestos. As a method for supporting the inorganic catalyst on such a carrier, a conventional method may be used, that is, a method in which the carrier is soaked in the catalyst aqueous solution and dried and supported. On the other hand, the method of contacting the compound of formula (II) with the catalyst is to pass the liquefied or vaporized diimine compound through the column (Culumn) filled with the catalyst, the temperature of the column is about 200 It is good to keep at about 400 degreeC.

If the temperature of the column is below 200 ° C., the synthesis reaction does not occur. On the contrary, if the temperature of the galum is above 400 ° C., carbonization occurs and the yield of indole decreases, thus maintaining the above temperature range. Good to do.

Another method other than the above is a method in which the diimine compound of the general formula (II) is brought into contact with a catalyst in advance and passed through a heated column.

Meanwhile, another operation method of the present invention includes a method of simultaneously flowing the aniline compound and glyoxal of the general formula (I) into a heated column (pyrolysis reaction tube) in a separate state, wherein each raw material is It may be vaporized and supplied to the column, or may be supplied in a liquid state to vaporize in the column, but for controlling the reaction, it is preferable to vaporize each raw material and then supply it to the column. In this case, a reactor may be used as a fixed bed reactor, a fluidized bed reactor, or a mobile bed reactor, and inert gases such as nitrogen, carbon dioxide, and underwater groups are used to alleviate the reaction rate.

In addition, when the hydrogen gas is used for dilution, the above catalytic activity is maintained for a long time, and thus the effect of the present invention can be further improved.

When a product such as formula (II) obtained by such an operation method is subjected to a distillation process, which is a general operation method, high yields of pure indole and its nuclear substituted derivatives are obtained.

The present invention will be described in detail with reference to Examples.

Example 1

A 500 cc round flask equipped with a stirrer and a thermometer was placed in a thermostat maintained at 50 ° C., and 150 g (1.61 mol) of aniline was added to the flask, followed by 29 g of freshly prepared glyoxal over 10 minutes with stirring at 200 rpm. 0.5 mole) is added dropwise. At this time, as glyoxal is added dropwise, a solid is formed immediately. After increasing the amount of the glyoxal and completing the dropwise addition of glyoxal for a complete reaction, the mixture is stirred for about 5 minutes. After cooling to 10 ° C., the resulting solid is filtered and dried to obtain about 92 g of diimine compound. When the product obtained as described above is mixed and ground with 5 g of magnesium sulfate and stirred in a small amount in a flask heated to 300 ° C., a gas is obtained in this process. When the gas is condensed and collected again, the indole is fractionated. And aniline are obtained separately.

At this time, the yield and yield of indole (mp: 52 to 54 ℃, bP: 253 to 254 ℃) are 40g and 68%, respectively, and the yield and yield of aniline (bp: 212 ℃) obtained as a by-product are 28g and 60%.

Example 2

Alumina is filled into a Pyrex glass tube having a diameter of 25 mm and a length of 30 cm, and a Y-shaped tube is connected to the supply port, and an air-cooled discharge port is installed at the discharge port.

At this time, 93 g (1 mol) of aniline and 5.8 g (0.1 mol) of glyoxal are simultaneously supplied in a liquid state for 20 minutes through the Y-tube while the temperature of the glass tube is maintained at 350 ° C.

The resulting mixture was analyzed by gas chromatography (gas chromatography), the conversion was 64%, the selectivity was 82%.

Examples 3-8

This Example is the same as in Example 2, but the same process, the reaction was carried out by supporting the catalyst on the alumina carrier is shown in Table 1 below.

TABLE 1

As described above, the most important step in synthesizing indole and its nuclear substituted derivatives is a method for preparing a diimine compound such as Formula (II), which is conventionally used with aniline to prepare the diimine. For example, although 1, 2-diol or 1, 2-dichloro compound and 1, 1, 2, 2-4 salt compound and the like were used, in the present invention, the diimine compound as described above was prepared by adding glyoxal to aniline. In this case, in order to convert the mixture to the diimine compound, the presence of a catalyst is necessary in the past at a high temperature. However, in the present invention, the reaction can be carried out without a catalyst even at a low temperature. In the prior art, although an expensive catalyst was used for treatment, in the present invention, it is possible not only to use the catalyst but also to use the catalyst. If there is a more efficient thermal decomposition process proceeds it is possible to obtain a high yield of indole and its nuclear substituted derivative thereof as illustrated in the Examples.

In addition, in the present invention, a mixture obtained by pyrolysis can be obtained through in general distillation, which is a general operation method, to obtain indole and its nuclear substituted derivatives having higher purity, and as a by-product, aniline derivatives are precipitated together with indole. As it can be reused as an economical and rational method, it can be adopted as an industrial manufacturing method and can make a great contribution to the field of organic chemistry.

Claims (3)

In preparing the indole and its nuclear substitution derivatives, glyoxal is added to the following general formula (I) of the aniline and its nuclear substitution derivative, and the molar ratio is added so as to be 0.5 to 20: 1 so that the temperature is 15 ° to 150 ° C. And a pyrolysis of the compound of formula (II), which is formed therein, with or without a catalyst to produce an indole compound represented by the following formula (III).

(However, X is an alkyl group, nitro group, hydroxy group or halogen group having 1 to 4 carbon atoms, n is an integer of 0 to 4, when n≥2, X may include at least two or more functional groups.) The method according to claim 1, wherein the aniline or a nuclear substituted derivative thereof is separated from glyoxal and introduced into a pyrolysis reaction tube. The process according to claim 1, wherein the catalyst is made using a metal salt corresponding to group IIa of the periodic table.