JPS603068B2 - Method for producing N-substituted imidazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing N-substituted imidazole derivatives having the general formula.

In the above formula, R1, R2 and R3 are the same or different and represent a hydrogen atom or a hydrocarbon residue, and R4 represents an alkyl group or an aralkyl group.

In the general formula (1), R1, R2 and R3 are preferably the same or different and are hydrogen atoms; methyl, ethyl,
n-propyl, n-butyl isobutyl, n-bentyl,
isobentyl, n-hexyl, isohexyl, hebutyl, octyl, nonyl, decyl, undecyl, dodecyl,
A linear or branched alkyl group having 1 to 1 carbon atoms such as tridecyl; an aryl group such as phenyl and naphthyl; R4 is methyl, ethyl, n-propyl, n-butyl, isobutyl, n-bentyl, isobentyl, n-hexyl, isohexyl, heptyl,
A linear or branched alkyl group having 1 to 1 carbon atoms such as octyl, nonyl, undecyl, dodecyl, and tridecyl; an alkylene moiety in the side chain having 1 to 2 carbon atoms such as penzyl and phenethyl represents an aralkyl group.

Conventionally, there are many documents regarding the synthesis method of N-substituted imidazole derivatives, including Elderfield (E1dem
eld): Heterocyclic Chemistry Vol. 5, p. 205 (1957) and Large Organic Chemistry Vol. 15, p. 17 (1957).
The outline is described in the 19th Spotted Year (Asakura Shoten),
Generally, a method for introducing an alkyl group or an aralkyl group into the nitrogen atom of imidazoles is to condense an aralkyl halide or aralkyl halide corresponding to the imidazole by dehydrohalogenation in the presence of a basic enigmatic agent. is used.

For example, in Japanese Patent Publication No. 43-123, there is a description of an example in which substitutable nitrogen atoms are alkylated with imidazoles and aralakyl halides in good yields.
These methods are known, except for imidazoles with special substituents. However, these methods are not only disadvantageous from an economic point of view because they use halide compounds, which are relatively difficult to manufacture, as raw materials, but also, depending on the type of halide, as described in Hakama Kosho No. 491-41435. In addition, the halide itself is not easy to handle in many cases, so it cannot be said that this method is still fully satisfactory as an industrial production method. From this technical background, research has been carried out on a method of dehydrative condensation using a corresponding alcohol as a raw material instead of the halide described above. For example, in Hakama Kosho No. 4718, alkyl or arylimidazoles and alcohols or ethers are mixed over catalysts (particularly preferably (heated to a temperature of 300 to 400°C) to cause a reaction, and then the resulting mixture is fractionated, or in Japanese Patent Publication No. 49-41435, a strong non-oxidizing mineral acid and a Lewis acid are reacted. By conducting the reaction in the liquid phase in coexistence, dehydration condensation is successful and the desired N
-Produces substituted imidazoles. However, the former method requires care in the preparation of the catalyst, and at reaction temperatures below 30 mm, decomposition by-products tend to mix into the reaction product, and when the reaction is carried out using these catalysts in the liquid phase, had the drawback that the yield was extremely high and the reaction had to be carried out at high temperature in the gas phase.

Moreover, in such a gas phase reaction, it is necessary to use raw material alcohols in large quantities, and most of the alcohol used is dehydrated on a catalyst and converted into olefins or ethers, making it extremely difficult to recover the alcohol. It was difficult. In addition, the latter method uses a Lewis acid and requires the reaction to be carried out in an anhydrous system. Therefore, it is not a general industrial method for producing N-direct imidazole derivatives, including drying the raw materials or the solvent used. is not appropriate. The present inventors conducted various searches in order to improve the shortcomings of such a secondary method and to find a catalyst for the condensation reaction of imidazoles and alcohols in a liquid phase with a good yield. phosphoric acid,
By using phosphoric anhydride or phosphate salts, even if the raw material or catalyst is used in a hydrated state, there are few creation products, and we succeeded in obtaining the target product in an extremely good yield.As a result of further intensive research, we found that N- The present invention has been completed by being able to be generalized as a new industrial production method for substituted imidazole derivatives.

The derivative having the general formula (1) obtained by the method of the present invention is a compound useful as a medicine, an agricultural chemical, or an intermediate thereof.

Representative examples of the N-substituted imidazole derivatives having the general formula (1) obtained by the method of the present invention are listed below, but the compounds obtainable by the method of the present invention are not limited thereby.

■1-Methylimidazole ■1,2-dimethylimidazole ■1-n-butyl-2-methylimidazole ■1-methyl-2-phenylimidazole ■1,2,4-trimethylimidazole ■1-dodecylimidazole ■1-dodecyl -2-methylimidazole ■1 dodecyl-2 rifhenylimidazole ■1 dodecyl-2-methyl-4-phenylimidazole ■1-dodecyl-4,
5-dimethylimidazole ■ 1-penzyl-2-methylimidazole ■ 1-penzyl-2,4-diphenylimidazo--nole ■ 1-tridecylimidazole According to the method of the present invention, the general formula (1) A compound having the general formula (wherein R1, R2 and R3 have the same meanings as described above).

) with the imidazole compound having the formula R4-OH
(m) (In the formula, R4 has the same meaning as described above.

) in the presence of phosphoric acid, phosphoric anhydride or phosphate. In carrying out the method of the present invention, the reaction is carried out by contacting the compound having the general formula (0) with the compound having the general formula (m) in the presence of a catalyst such as phosphoric acid, phosphoric anhydride or a phosphate. It is done.

The quantitative relationship between the compound having the general formula (0) and the compound having the general formula (m) is not particularly limited, but a stoichiometric ratio of each is sufficient. In this case, most of the alcohol compound (m) used participates in the reaction, which is economically extremely advantageous compared to the above-mentioned known gas phase reaction. The soot used in this reaction is:
Phosphoric acid such as orthophosphoric acid, pyrophosphoric acid or polyphosphoric acid; Phosphoric anhydride; Alkali metal dihydrogen phosphate or ammonium dihydrogen phosphate such as sodium dihydrogen phosphate or potassium dihydrogen phosphate: General formula (1) or (D) It is a phosphate of an imidazole compound with These catalysts can be used as they are not only in anhydrous forms but also in hydrated forms, and in the case of the above salts, they may be used after being prepared in advance, but they can also be used by adding a base and phosphoric acid to the reaction system. It also shows good catalytic activity depending on the method. Furthermore, the abovementioned catalysts can be used alone or in any mixtures with one another in the reaction. Generally, the catalyst is 1 to 5% by weight based on the raw material imidazole compound having the general formula (0),
It is particularly preferably used in a proportion of 5 to 3% by weight, and can be recovered and used again after the reaction. The reaction temperature is usually 60 to 300 qo, particularly preferably 200 to 2
The reaction is carried out in a liquid phase at around 7.0 mm using a normal Takaazusa type reaction vessel and heating under normal pressure (pressure is applied only when special low boiling point alcohols (m) are used).
The reaction time varies mainly depending on the reaction temperature, etc., but is about 2 to 1 hour, and can be shortened by increasing the amount of shark soot. Therefore, the reaction can generally be carried out as follows. That is, the raw material compounds having the general formulas (0) and [m) are mixed in a reaction vessel, a catalyst is added under a sieve, and the mixture is heated. At this time, the reaction can proceed even more smoothly by sequentially removing mixed or generated water. After the reaction is completed, the target compound having the general formula (1) is collected from the reaction mixture according to a conventional method.

For example, after completion of the reaction, the target compound can be isolated by fractional distillation of the reaction mixture. As described above, according to the method of the present invention, alcohols that are easy to handle can be used as raw materials, and the raw materials or catalysts can also be provided in a liquid phase in a water-containing state. It has the advantage that the reaction can be carried out with a simple device without requiring a high-temperature gas-phase reactor or a reaction under special conditions such as under moisture-proof conditions. This method provides an industrially extremely advantageous method since it can produce the target N-imidazole derivative in an extremely good yield with few side reactions. Next, the method of the present invention will be explained in more detail with reference to Examples.

Parts in the examples mean parts by weight. Example 11-Dodecylimidazolimidazole Isobe, 186 parts of 1-dodecyl alcohol and 3.4 parts of 85% phosphoric acid are mixed and reacted at 260°C for 15 hours.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 15
1-152℃/1. Target compound 212 with W pig day
Guo is obtained. This is 90% of the raw material imidazole
Corresponds to the yield. Example 2 1-Dodecyl-2-methylimidazole 82 parts of 2-methylimidazole, 186 parts of 1-dodecyl alcohol and 16.4 parts of 85% phosphoric acid were mixed,
React for 1q hours at 0°C.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 17
213 parts of the target compound having a temperature of 4 to 176°C/3 days are obtained. This corresponds to a yield of 85% based on the raw material 2-methylimidazole. Example 3 144 parts of 1-dodecyl-2-phenylimidazole, 186 parts of 1-dodecyl alcohol and 29 parts of 85% phosphoric acid were mixed,
React for 1 q hour at 0 qo.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 18
Target compound 275 with 7-189°C/0.1 side temperature
part is obtained. This corresponds to the percentage yield based on the starting material 2-phenylimidazole. Example 4 1-penzyl-2-methylimidazole 82 parts of 2-methylimidazole, 1 part of benzyl alcohol
Mix 08 parts of 85% phosphoric acid and 16.4 parts of 85% phosphoric acid, and heat at 220°C.
Let it react for 1 feeding time.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 14
A patch of the target compound 1 having a temperature of 0 to 141°C/4 sides is obtained. This is 8 for the raw material 2-methylimidazole.
Corresponds to 0% yield. Example 5 1-Dodecylimidazole When reacted and treated in the same manner as in Example 1 using the catalyst listed in the attached table,
Each of the target compounds was obtained in the yield shown in the separate table.

Example 9 1-Dodecylimidazolimidazole Oribe, 186 parts of 1-dodecyl alcohol, and 20.4 parts of 1-dodecyl imidazole phosphate are mixed and reacted at 260°C for 10 hours.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 15
1 to 15 are ○/1. 22 units of the target compound having opposite positions are obtained. This is 93% of the raw material imidazole.
Corresponds to the yield. Example 10 1,2-Dimethylimidazole 82 parts of 2-methylimidazole, 64 parts of methanol and 14 parts of pyrophosphoric acid were mixed and heated under pressure at 200 qo.
Allow time to react.

After the reaction is complete, the reaction mixture is subjected to fractional distillation, resulting in a boiling point of 20
86 parts of the target compound having a molecular weight of 3 to 205 o0 are obtained.
This corresponds to a yield of 90% based on the starting material 2-methylimidazole. Example 11 1-n-butyl-2-methylimidazole 82 parts of 2-methylimidazole, 148 parts of n-butanol and 85 parts of n-butyl-2-methylimidazole
% phosphoric acid and reacted under pressure at 200° C. for 1q hours.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 13
104 parts of the target compound having a temperature of 0 to 131°C/2 are obtained. This corresponds to a yield of 75% based on the raw material 2-methylimidazole. Example 12 1-Methyl-2-phenylimidazole 144 parts of 2-phenylimidazole, methanol and 14 parts of 85% phosphoric acid were mixed and heated at 200°C under pressure.
Allow to react for q hours.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 13
142 parts of the target compound having a ratio of 0 to 13100/2 are obtained. This corresponds to a yield of 90% based on the raw material 2-phenylimidazole. Example 13 1,2,4-trimethylimidazole 96 parts of 2,4-dimethylimidazole, 96 parts of methanol
and 15 parts of 85% phosphoric acid, and 200q under pressure.
React for lq hours at o.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 11
105 parts of the target compound having a temperature of 0 to 111° C./2 are obtained. This corresponds to a yield of 95% based on the raw material 2,4-dimethylimidazole. Example 14 1-dodecyl imidazole To 35 parts of the distillation residue of Example 1, imidazole spots and 186 parts of 1-dodecyl alcohol were newly added, and 26 parts of 1-dodecyl imidazole was added.
React for 15 hours at zero temperature.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 15
A base of the target compound 22 having a temperature of 1 to 152°C/1 skin temperature is obtained. This corresponds to a yield of 93% based on the raw material imidazole. Example 15 1-Tridecyl imidazole Isobe, 2 parts of 1-tridecyl alcohol, and 14 parts of 85% phosphoric acid are mixed and reacted at 26°C for 1q hours.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 17
233 parts of the target compound having a temperature of 0-171° C./4 days are obtained. This corresponds to a yield of 93% based on the raw material imidazole. Example 16 1 Dodecyl imidazole Isobe, 186 parts of 1 dodecyl alcohol, and 14 parts of polyphosphoric acid are mixed and reacted at 27 ppm for 3 hours.

Claims (1)

[Claims] 1 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2 and R^3 are the same or different and represent a hydrogen atom or a hydrocarbon residue.) An imidazole compound having the formula R^4-OH (III) (in the formula, R^4 represents an alkyl group or an aralkyl group) is reacted with an alcohol having the formula ▲Mathematical formula, chemical formula, table, etc.▼ In the formula, R^1, R^2, R^3 and R^4 have the same meanings as defined above.) When producing an N-substituted imidazole derivative having 1 selected from salts, ammonium dihydrogen phosphate salts, phosphates of imidazole compounds having formula (I) and formula (II)
A method for producing an N-substituted imidazole derivative having the formula (I), characterized in that one or more phosphates are present.