JPS5938229B2 - Method for producing N-substituted imidazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new process for the preparation of N-substituted imidazole derivatives having the general formula N:' NN(I).

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 (I), R'', R2 and R3 are preferably the same or different and are hydrogen atoms; methyl, ethyl,
Straight chain or having 1 to 13 carbon atoms such as n-propyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl Branched alkyl group; represents an aryl group such as phenyl or naphthyl; R4 is methyl, ethyl, n
-propyl, n-butyl, isobutyl, n-pentyl,
Straight-chain or branched alkyl groups having 1 to 13 carbon atoms such as isopentyl, n-hexyl, isohexyl, heptyl, octyl, nonyl, undecyl, dodecyl, and tridecyl; side chains such as benzyl and phenethyl; represents an aralkyl group in which the alkylene moiety has 1 to 2 carbon atoms.

Conventionally, there are many documents regarding the synthesis method of N-substituted imidazole derivatives, including Elderfield (Elderfield).
field): Heterocyclic chemistry (H
eter Ocyclic Chemistry) Vol.
205 pages (1957) and Large Organic Chemistry Volume Y1, 1
77 (1958, Asakura Shoten), the general method for introducing an alkyl group or an aralkyl group into the nitrogen atom of an imidazole is to introduce an alkyl halide or an aralkyl halide corresponding to the imidazole into a base. A method of condensation by denohydrogenation in the presence of a sexual reagent is used.

For example, Japanese Patent Publication No. 43-12354 describes an example in which substitutable nitrogen atoms are alkylated with imidazoles and alkyl halides in good yields. These methods are otherwise known. However, these methods are not only disadvantageous from an economic point of view because they use halide compounds that are relatively difficult to manufacture as raw materials, but depending on the type of halide, the method described in Japanese Patent Publication No. 49-41435 As such, 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 Japanese Patent Publication No. 47-5939, alkyl or arylimidazoles and alcohols or ethers are reacted over a catalyst (particularly preferably 300 to 400 After conducting the reaction by conducting the mixture to (heated to a temperature of By carrying out the reaction in each phase, dehydration condensation was successful in producing the target N-monosubstituted imidazoles. However, the former method requires care in the preparation of the catalyst, and at reaction temperatures below 300°C, decomposition byproducts are likely to be mixed into the reaction product, and when the reaction is carried out using these catalysts in the liquid phase, The yield was extremely poor, and therefore 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 a large excess of alcohol as a raw material, and most of the alcohol used is dehydrated on a catalyst and converted into olefin or ether, making it extremely difficult to recover the alcohol. Ta. 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 common industrial method for producing N-substituted imidazole derivatives, including drying the raw materials or the solvent used. It's not appropriate.

In order to improve the drawbacks of such conventional methods, the present inventors have developed a method that allows the reaction to proceed sufficiently and gives good results in terms of yield even when the raw materials or catalysts are used in a liquid phase and in a water-containing state. We conducted a search for a catalyst for the same, and found that by using sulfuric acid or sulfate even in a liquid phase reaction, the reaction between imidazoles and alcohols or ethers described above can proceed easily and does not require anhydrous conditions. As a result of further intensive research, it was possible to generalize the method as a new industrial production method for N-substituted imidazole derivatives, and the present invention was completed.

The derivative having the general formula () obtained by the method of the present invention is a compound useful as a medicine, agricultural chemical, or an intermediate thereof.〇 The derivative having the general formula (1) obtained by the method of the present invention Representative examples of monosubstituted imidazole derivatives are listed below, but the compounds obtained by the method of the present invention are not limited thereby.

According to the method of the present invention, the compound having the general formula (1) is formed by the general formula (where Rl, R2 and R3 have the same meanings as described above).

) is an imidazole compound having the general formula (wherein R4 has the same meaning as described above).

It can be obtained by reacting alcohols or ethers having : with sulfuric acid or sulfate in the presence of sulfuric acid or sulfate.
In carrying out the method of the present invention, the reaction is carried out using the general formula (
) is brought into contact with the compound having the general formula (1) or (IV) in the presence of a catalyst such as sulfuric acid or a sulfate.

The quantitative relationship between the compound having the general formula () and the compound having the general formula (1) or (5) is not particularly limited, but a stoichiometric ratio of each is sufficient.

In this case, most of the alcohol compound (2) used participates in the reaction, which is economically extremely advantageous compared to the above-mentioned known gas phase reaction. Sulfates used as catalysts in this reaction include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as beryllium, magnesium, calcium, and barium, aluminum, copper, zinc, titanium, vanadium, chromium, and manganese. Salts of metals such as iron, cobalt and nickel, ammonia and tertiary organic amines can be used, but particularly preferred are sulfuric acids such as sodium monohydrogen sulfate and potassium monohydrogen sulfate in the case of alkali metals. Monohydrogen metal salts: beryllium sulfate, magnesium sulfate for alkaline earth metals; aluminum sulfate, copper sulfate, ferric sulfate, cobalt sulfate, nickel sulfate for other metals; ammonium hydrogen sulfate, ammonium sulfate, etc. ammonium salt; sulfuric acid gun) double salts such as ammonium, iron sulfate (1) ammonium, potassium alum, iron alum: sulfate of the imidazole compound having the above general formula (1) or (), triethylamine, pyridine; Examples include organic amine sulfates such as sulfates of tertiary organic amines. These catalysts can be used as they are, not only in anhydrous forms but also in hydrated forms, and for the above salts, they may be prepared in advance before use, but they can also be used by adding a base and sulfuric acid to the reaction system. It also exhibits good catalytic activity by the method. Also, instead of sulfuric acid, its dehydrated derivative pyrosulfuric acid or its salts such as potassium pyrosulfate can be used. Furthermore, the abovementioned catalysts can be used alone or in any mixtures with one another in the reaction. Furthermore, the yield of the target N-substituted imidazole compound can be increased by using oxides of various metals in combination with the catalyst. Preferred examples of metals forming oxides used in combination include aluminum, titanium, thorium, calcium, and silicon. Generally, the catalyst weighs 1 to 50% by weight based on the raw material imidazole compound having the above general formula (). It is particularly preferably used in a proportion of 10 to 30% by weight, and can also be recovered and reused after the reaction. The reaction temperature is usually 60 to 300 ℃
°C, particularly preferably around 200 to 300 °C, in a liquid phase using an ordinary stirred reaction vessel under normal pressure (only when using special low-boiling alcohols (1) or ethers (5)) This is done by heating under pressure (under pressure).
The reaction time varies mainly depending on the reaction temperature and the like, but is about 2 to 15 hours, and can be shortened by increasing the amount of catalyst. Therefore, the reaction can generally be carried out as follows. That is, the general formula () and () or (5
) are mixed in a reaction vessel, a catalyst is added under stirring, and the mixture is heated. At this time, the reaction can be made to proceed even more smoothly by successively distilling off water present or produced. 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 the reaction is complete, 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 or ethers that are easy to handle can be used as raw materials,
Moreover, since the raw material or catalyst can be provided in a liquid phase and in a water-containing state, there is no need for a reaction under special conditions such as a high-temperature gas phase reactor or a moisture-proof environment in conventional known methods. It has the advantage of being able to carry out the reaction using an apparatus, and also has the advantage that there are few side reactions to olefins or ethers, etc., and the target N-substituted imidazole derivative can be obtained in extremely good yields, making it extremely advantageous industrially. The present invention provides a method. 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-Dodecylimidazole 68 parts of imidazole, 559 parts of 1-dodecyl alcohol and 17 parts of sulfuric acid are mixed and reacted at 235°C for 10 hours.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 15
153 parts of the target compound having a temperature of 1-152°C/1 mmHg are obtained. This is 64.7 based on the raw material imidazole.
Corresponds to % yield. Example 2 68 parts of 1-dodecyl imidazole imidazole, 532 parts of didodecyl ether and 34 parts of potassium hydrogen sulfate are mixed and reacted at 300°C for 15 hours.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 15
123 parts of the target compound having a H9 of 1 to 152°C/one batch are obtained. This is 52.3% of the raw material imidazole.
Corresponds to the yield. Example 3 68 parts of 1-ethylimidazoleimidazole, 69 parts of ethanol and 34 parts of potassium hydrogen sulfate were mixed and heated at 180°C for 10 minutes in a pressure-resistant container.
Allow time to react.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 11
67 parts of the target compound having compound 8-119 C/8071tmHg are obtained. This is 7 for the raw material imidazole.
Corresponds to a yield of 0%. Example 4 1-Benzyl-2-methylimidazole 82 parts of 2-methylimidazole, 3 parts of benzyl alcohol
24 parts and 20 parts of sulfuric acid were mixed and reacted at 210°C for 10 hours.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 11
Target compound 10 having a temperature of 8 to 121°C/2mmHf1
6 parts are obtained. This corresponds to a yield of 61.6% based on the raw material 2-methylimidazole. Example 5 68 parts of 1-dodecyl imidazole imidazole, 559 parts of 1-dodecyl alcohol, 17 parts of aluminum sulfate and 17 parts of γ-alumina are mixed and reacted at 250°C for 20 hours.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 15
177 parts of the target compound having a temperature of 1-152° C./1 mmHg are obtained. This corresponds to a yield of 75% based on the raw material imidazole. Example 6 1-Methyl-2-phenylimidazole 144 parts of 2-phenylimidazole, 64 parts of methanol and 14 parts of potassium hydrogen sulfate were mixed, and 20 parts of potassium hydrogen sulfate were mixed under pressure.
React for 10 hours at 0'C.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 13
103 parts of the target compound having a temperature of 0 to 13 rC/2 mmHg are obtained. This corresponds to a yield of 65% based on the raw material 2-phenylimidazole. Example 71, 2, 4-
Trimethylimidazole 96 parts of 2,4-dimethylimidazole, 96 parts of methanol
10 parts and 10 parts of sulfuric acid were mixed and heated at 200°C under pressure for 10 parts.
Allow time to react.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 11
74 parts of the target compound having a temperature of 0-112°C/2mmH9 are obtained. This corresponds to a yield of 67% based on the raw material 2,4-dimethylimidazole. Example 8 68 parts of 1-dodecyl imidazole imidazole, 186 parts of 1-dodecyl alcohol, 25 parts of potassium hydrogen sulfate and 20 parts of γ-alumina are mixed and reacted at 250° C. for 15 hours.

After the reaction is complete, the reaction mixture is subjected to vacuum distillation, resulting in a boiling point of 15
156 parts of the target compound having a temperature of 1-152°C/IllH9 are obtained. This corresponds to a yield of 66% based on the raw material imidazole. Examples 9 to 19 1-Dodecylimidazole When reacted and treated in the same manner as in Example 1 using the catalyst shown in the attached table,
Each of the target compounds was obtained in the yield shown in the separate table.

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 or R^4-O-R^4 (where R^
4 represents an alkyl group or an aralkyl group. ) in the presence of sulfuric acid or sulfate. Production of N-substituted imidazole derivatives having the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Law.