JP2003306480A - Method for producing 4,6-dimetylindole and supported catalyst - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an indole derivative without fear of corrosion of an apparatus in high selectivity from anilines by utilizing a catalyst which can readily be prepared, capable of recovering expensive anilines used in a largely excess amount and reutilizing the anilines. <P>SOLUTION: The method for producing 4,6-dimethylindole comprises reacting 3,5-xylidine with ethylene glycol in a liquid phase in the presence of a catalyst in which an element of the group VIII is supported with a carrier. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing 4,6-dimethylindole from 3,5-xylidine and a supported catalyst.

[0002]

[Prior art]

[Patent Document 1] JP-A-62-93237

[Patent Document 3] Japanese Patent Laid-Open No. 64-38064

[Non-Patent Document 1] Bulletin of the Korean Chem.So
c., (1999), p.119-21

Dimethylindole is a compound useful as an intermediate for medicines and agricultural chemicals.

Conventionally, as a method of producing an indole derivative, a method of reacting an aniline and a 1,2-glycol in a liquid phase in the presence of a metal catalyst is known.
One such method is

[Patent Document 1],

[Patent Document 2] and

[Non-Patent Document 1] is known.

However, in the above conventional technique, 1, 2
-It was necessary to use a large excess of anilines, which are more expensive than glycols. Therefore, in order to inexpensively industrially produce an indole derivative, it is important that the yield is high, the amount of by-products derived from anilines is small, and the selectivity based on anilines is high.

[0006]

Patent Document 1 discloses a method using a metal-containing compound containing ruthenium or rhodium as a catalyst. However, since it is necessary to synthesize a metal compound or generate it in a reaction system, and since a metal halide that may corrode the equipment is used as a raw material of the metal compound,

The method described in Patent Document 1 is not satisfactory as an industrial manufacturing method.

[0007] Also

[Patent Document 2] discloses a method for producing an indole derivative by reacting anilines and 1,2-glycols in a liquid phase using a specific metal catalyst. However, there is no description or suggestion of the difference in the yield and selectivity of the target product based on the difference in the structure of the substrate, and the Examples only exemplify the synthesis of indole from aniline and ethylene glycol.

[0008]

In [Non-Patent Document 1], various indole derivatives are synthesized by reacting ethylene glycol with various anine phosphoruss in the presence of a complex catalyst of ruthenium chloride-triphenylphosphine-tin chloride catalyst. From 2,3-dimethylaniline, 2,5-dimethylaniline and 3,5-dimethylaniline, 6,7-dimethylindole and
4,7-dimethylindole and 4,6-dimethylindole have been synthesized. However, in order to separate the complex catalyst ruthenium chloride-triphenylphosphine-tin chloride catalyst from the reaction solution after completion of the reaction, for example, a method by chromatography or distillation can be considered, but the separation by chromatography is complicated in operation. Therefore, in the separation by distillation, the complex catalyst may be decomposed, or the phosphines may be oxidized, so that the recovery may not be possible.

The method described in Non-Patent Document 1 is also not industrially satisfactory.

[0009]

The problem to be solved by the present invention is to produce dimethylindole from anilines with a high selectivity by using a catalyst which is easy to prepare, and without fear of corrosion of the equipment. It is an object of the present invention to provide a method in which a catalyst can be easily separated and recovered after completion of the reaction, and expensive anilines used in large excess can be recovered in high yield and reused.

[0010]

As a result of extensive studies on the reaction between anilines and 1,2-glycol, the present inventor selected 3,5-xylidine as a starting aniline and further specified it. The inventors have found that it is possible to specifically produce 4,6-dimethylindole with a high selectivity by selecting a supported catalyst, and have completed the present invention.

That is, the present invention is characterized in that 3,5-xylidine and ethylene glycol are reacted in a liquid phase in the presence of a catalyst having a Group VIII element supported on a carrier. The present invention relates to a method for producing dimethylindole.

Further, the present invention relates to a method for producing 4,6-dimethylindole, wherein the catalyst in which the Group VIII element is supported on a carrier is a ruthenium-supported catalyst.

Further, in the present invention, after the ruthenium-supported catalyst has adsorbed a ruthenium-containing compound on a carrier,
A ruthenium-supported catalyst prepared by reduction with sodium borohydride, 4,
The present invention relates to a method for producing 6-dimethylindole.

Furthermore, in the present invention, 3,5-xylidine and ethylene glycol are reacted in a liquid phase to give 4,6-
A supported catalyst for producing dimethylindole, wherein the supported catalyst is prepared by adsorbing a ruthenium-containing compound on a support and then reducing it with sodium borohydride. It is a thing.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The Group VIII element in the present invention is an element classified into Group VIII of the short periodic table, and specifically Fe, Co, Ni, Ru, Rh, Pd, P.
Examples thereof include t and the like.

The catalyst in which the Group VIII element used in the present invention is supported on the carrier is prepared by a conventional impregnation method, coprecipitation method, kneading method or a combination of these methods.
For example, in the impregnation method, a carrier suspended in water is added with a group VIII element-containing compound corresponding to a predetermined amount to be adsorbed on the carrier, and a reduction treatment is performed, followed by drying. To do. Since 4,6-dimethylindole can be obtained with a high selectivity based on 3,5-xylidine,
A ruthenium-supported catalyst is particularly preferable as the catalyst supporting the Group VIII element.

The supported catalyst of the present invention specifically synthesizes 4,6-dimethylindole using 3,5-xylidine as a substrate, and the substrate is 2,3-xylidine.
In the case of 2,4-xylidine and 2,5-xylidine, the corresponding 6,7-dimethylindole, 5,7-dimethylindole, 4,4, respectively, using the supported catalyst of the present invention, respectively.
The yield of 7-dimethylindole is low.

Examples of the group VIII element-containing compound include group VIII
Examples thereof include chlorides, carboxylates, oxides and complexes of group elements, such as ruthenium chloride hydrate, ruthenium oxide hydrate, hexaammine ruthenium chloride, tris (acetylacetonato) ruthenium, dodecacarbonyl triruthenium, Examples thereof include palladium chloride, palladium acetate, rhodium chloride, rhodium acetate and the like.

Any carrier may be used as long as it is inert under the reaction conditions, and examples thereof include activated carbon, silica, α-alumina, γ-alumina, silica-alumina, and various metal oxides and complex oxides. The activated carbon is preferable because it has a large surface area and the obtained catalyst has high activity.

The amount of the Group VIII element supported is 0.1 to 20% by weight. If it is less than 0.1% by weight, a large amount of catalyst is required to obtain the desired product with a sufficient yield, and it is difficult to industrially utilize it. Further, the yield of the target product is not improved even if the amount of the support exceeds 20% by weight.

As a method for the reduction treatment, a method usually used when preparing a supported catalyst can be used, and a method of reducing with a reducing agent such as sodium borohydride, hydrazine and formalin in a liquid phase, and a method of reducing hydrogen in a gas phase with hydrogen. There is a method of reduction.

The amount of sodium borohydride used at the time of reduction is preferably 0.5 times or more, and more preferably 3 times or more mol based on the ruthenium atom.

As the reduction method, a known method can be used, but it can be obtained by dropping an aqueous solution of sodium borohydride on a ruthenium compound-containing carrier suspended in water at room temperature. The catalyst obtained by the reduction operation can be washed with water before use.

The catalyst may be either a water-containing product or a dry product, but from the viewpoint of operability, a 40-60% water-containing product is preferable.

The method for producing 4,6-dimethylindole of the present invention is carried out by heating 3,5-xylidine and ethylene glycol in the presence of the supported catalyst thus prepared. It is preferable to use 3,5-xylidine in a 1- to 10-fold molar quantity versus ethylene glycol. When the amount of 3,5-xylidine used is less than the above range, the reaction proceeds slowly and requires a long time, which is not preferable. Further, when the amount of 3,5-xylidine used is larger than the above range, there is no particular problem, but from the economical point of view, the amount within the above range is sufficient.

The reaction is preferably carried out in an inert gas atmosphere, for example, a nitrogen gas atmosphere.

As the reaction solvent, a solvent which is inactive under the reaction conditions may coexist. Examples include organic solvents such as toluene, xylene and pyridine. The amount of the catalyst used is not particularly limited, but is usually in the range of 1 to 10% by weight based on ethylene glycol. If the amount of the catalyst used is less than the above range, the reaction proceeds slowly and requires a long time, which is not preferable. Further, when the amount of the catalyst used is larger than the above range, there is no particular problem, but from the economical point of view, the amount within the above range is sufficient.

The reaction temperature is in the range of 180 to 350 ° C, preferably 200 to 300 ° C. If the temperature is lower than 180 ° C, the reaction hardly progresses, and if it exceeds 350 ° C, by-products increase. The reaction time is 1 to 10 hours. In the method of the present invention, the 4,6-dimethylindole thus obtained can be easily separated and purified from the reaction product by a suitable method, for example, a conventional method such as distillation. The 3,5-xylidine used in large excess with respect to ethylene glycol can be recovered in high yield by distillation and can be used in the next reaction.

Further, in order to separate the supported catalyst of the present invention from the reaction solution after the completion of the reaction, a filtering means such as an ordinary filter press may be employed, and the separated catalyst can be easily separated and recovered.

The obtained 4,6-dimethylindole is hydrogenated by a commonly used method to convert it into an indoline derivative, and further to an indoline derivative in which the nitrogen atom of this indoline derivative is protected with an appropriate protecting group. be able to. Examples of the protective group include an acyl group such as an acetyl group and a benzoyl group, an alkyl such as a methoxycarbonyl group, an ethoxycarbonyl group and a benzyloxycarbonyl group, or an aralkyloxycarbonyl group, an alkyl group such as a methanesulfonyl group, a benzylsulfonyl group and a toluenesulfonyl group. , Aralkyl or arylsulfonyl groups and the like.

[0031]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

The conversion, selectivity and yield in the following examples and comparative examples were calculated by the following formulas.

Conversion of anilines (%) = (mol number of anilines added-mol number of anilines after reaction) / mol number of added anilines × 100

Selectivity of indole derivative based on anilines (%) = number of moles of indole derivative formed ÷
(Number of moles of added anilines-Number of moles of anilines after reaction) × 100

Yield (%) of indole derivative based on aniline = conversion rate (%) of aniline × selectivity of indole derivative based on aniline (%) ÷ 100

Production Example 1 Preparation of 5% Ruthenium Carbon Catalyst A (Reduction of Sodium Borohydride) 30 g of activated carbon and 300 ml of water were added to a 1L four-necked flask, and the mixture was heated with stirring at 50 ° C., and a 20% caustic soda aqueous solution was added to adjust the pH of the mixed system. 12
Added until. While maintaining the temperature of the mixed system at 50 to 55 ° C, a solution prepared by dissolving 3.8 g of ruthenium (III) chloride hydrate in water was added dropwise, and the mixture was stirred for 1 hour. Mixing system temperature 30 ℃
After cooling to below, sodium borohydride 12
A solution of g in water was added dropwise to reduce the ruthenium compound, which was filtered and washed with water to give a 5% ruthenium carbon catalyst A.
Was prepared.

Production Example 2 Preparation of 5% Ruthenium Carbon Catalyst B (Hydrogen Reduction) 30 g of activated carbon and 300 ml of water were added to a 1L four-necked flask and stirred at room temperature, and then 3.8 g of ruthenium (III) chloride hydrate was dissolved in water. The resulting solution was added dropwise and stirred for 1 hour. Next, the mixed system was concentrated and dried to prepare ruthenium chloride-supporting activated carbon, which was then reduced in a hydrogen stream at 500 ° C. to prepare a 5% ruthenium carbon catalyst B.

EXAMPLE 1 72.7 g (0.6 mol) of 3,5-xylidine and 12.4 g (0.2 mol) of ethylene glycol were placed in a SUS autoclave equipped with a stirrer and having an internal capacity of 200 ml, and the ruthenium prepared in the above Production Example 1 was used. Carbon catalyst A (Ru content 5% by weight)
After adding 93 g, the air in the autoclave was replaced with nitrogen gas, and the reaction was carried out while stirring the autoclave at a reaction temperature of 235 ° C. for 3 hours. After the reaction, the catalyst was filtered off from the reaction solution, and the reaction product was analyzed by gas chromatography. The conversion of 3,5-xylidine was 26%, and the selectivity based on 3,5-xylidine was 90%, 3,5. -It was confirmed that 4,6-dimethylindole was produced at a yield of 23% based on xylidine. By distilling the reaction solution from which the catalyst was filtered off, unreacted 3,5-xylidine 46.3
g was obtained.

Example 2 A reaction was conducted in the same manner as in Example 1 except that the ruthenium carbon catalyst B was changed to the ruthenium carbon catalyst B prepared in Production Example 2 above. As a result, the conversion rate of 3,5-xylidine was 33.
%, 3,5-xylidine-based selectivity 53%, 3,5-
It was confirmed that 4,6-dimethylindole was produced at a yield of 17% based on xylidine.

Example 3 A reaction was carried out in the same manner as in Example 1 except that the ruthenium carbon catalyst was changed to a palladium carbon catalyst. As a result, 3,5
-The conversion of xylidine is 6%, the selectivity based on 3,5-xylidine is 77%, and the yield based on 3,5-xylidine is 5%.
Then, it was confirmed that 4,6-dimethylindole was produced.

Example 4 The same reaction as in Example 1 was carried out except that 3,5-xylidine collected in Example 1 was used and the reaction scale was set to 2/3. As a result, the conversion rate of 3,5-xylidine was 23.
%, 3,5-xylidine standard selectivity 84%, 3,5
-It was confirmed that 4,6-dimethylindole was produced in a yield of 19% based on xylidine.

Comparative Example 1 Reaction was carried out in the same manner as in Example 1 except that 3,5-xylidine was changed to the anilines shown in Table 1 below.

[0043]

[Table 1]

As is clear from the results shown in Table 1, 3,5-
It can be seen that when anilines other than xylidine were selected, the selectivity and yield were lower than those in Example 1 in all cases.

Comparative Example 2 Reaction was carried out in the same manner as in Example 1 except that ethylene glycol was changed to 2,3-butanediol. as a result,
The conversion of 3,5-xylidine is 26%, the selectivity based on 3,5-xylidine is 34%, the yield based on 3,5-xylidine is 9%, and 2,3,4,6-tetramethylindole is produced. Admitted that.

[0046]

According to the present invention, a catalyst which is easily prepared by reacting 3,5-xylidine with ethylene glycol in a liquid phase in the presence of a catalyst having a Group VIII element supported on a carrier. So, with high selectivity from 3,5-xylidine,
In addition, 4,6-dimethylindole can be obtained without worrying about corrosion of the equipment. Therefore, expensive 3,5-xylidine used in large excess can be effectively utilized.

Further, by using a ruthenium-supported catalyst prepared by reduction with sodium borohydride, 4,6-dimethylindole can be produced with higher selectivity.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4C204 AB05 BB04 CB03 DB01 EB01                       FB01 GB03                 4G069 AA03 AA08 BA08A BA08B                       BB02A BB02B BC69A BC70A                       BC70B CB25 CB67 FA02                       FB14 FB45                 4H039 CA42 CH10

Claims (4)

[Claims] 1. A process for producing 4,6-dimethylindole, which comprises reacting 3,5-xylidine with ethylene glycol in a liquid phase in the presence of a catalyst having a Group VIII element supported on a carrier. Method. 2. The method for producing 4,6-dimethylindole according to claim 1, wherein the catalyst having a Group VIII element supported on a carrier is a ruthenium-supported catalyst. 3. The ruthenium-supported catalyst according to claim 2, wherein the ruthenium-supported catalyst is a ruthenium-supported catalyst prepared by adsorbing a ruthenium-containing compound on a carrier and then reducing the same with sodium borohydride. 6
-Method for producing dimethylindole. 4. A supported catalyst for producing 4,6-dimethylindole by reacting 3,5-xylidine with ethylene glycol in a liquid phase, the supported catalyst adsorbing a ruthenium-containing compound on a carrier. The supported catalyst is characterized by being prepared by reducing with sodium borohydride after heating.