JP4442952B2 - Process for producing 5-formylimidazoles - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing 5-formylimidazoles such as 2-alkyl-5-formylimidazole useful as a raw material for pharmaceuticals such as diuretics and antihypertensives.
[0002]
[Prior art]
Alkylformylimidazole has a useful use as described above, and is a chemical product that has been attracting attention in recent years, but there are not many known literatures regarding its production method. For example, 2-alkyl-5-hydroxymethylimidazole is used as a starting material, Reagent oxidation methods using heavy metals and oxidation methods using nitric acid have been studied.
[0003]
[Problems to be solved by the invention]
However, in such a technique, in the former case, a great deal of labor is required for handling heavy metals and processing of the waste catalyst, and in the latter case, in terms of yield of the target product and generation of nitrogen oxides, etc. It is difficult to say that it is very disadvantageous and satisfactory for implementation on a scale. Therefore, development of a new method for producing 2-alkyl-5-formylimidazole, which avoids such problems and can produce the target product in an industrially safe manner and in a high yield, is strongly desired among those skilled in the art. As a result of intensive researches to achieve such an object, the present applicant has previously conducted catalytic oxidation of 2-alkyl-5-hydroxymethylimidazole in the presence of a noble metal catalyst, particularly in a reaction in an alkaline water solvent. We found that the object can be achieved advantageously, and filed a patent application.
However, since an expensive precious metal catalyst is used in such a reaction, it has been frequently studied from the view that it is desirable to reduce the amount used in an industrial scale as much as possible. The problem of leading to destabilization of the product and thus reducing the yield of the target product could not be easily solved.
[0004]
[Means for Solving the Problems]
However, the present inventor introduces oxygen or air in the presence of a noble metal catalyst and catalytically oxidizes 5-hydroxymethylimidazoles represented by the following general formula (1) in an alkaline water solvent to form the following general formula ( In producing the 5-formylimidazoles shown in 2), when the reaction is carried out while maintaining the dissolved oxygen content in the reaction solution at 5 ppm or less, the 5-formylimidazoles are collected even if the amount of the catalyst used is reduced. The inventors have found that it can be produced efficiently, and have completed the present invention.
[Chemical 1]
(In the formula, R is hydrogen or an alkyl group having 1 to 5 carbon atoms, and the hydrogen bonded to the 4-position carbon may be substituted with halogen, an alkyl group having 1 to 12 carbon atoms or a substituted alkyl group. .)
[0005]
DETAILED DESCRIPTION OF THE INVENTION
The reaction of the present invention is represented by the following formula ( 3 ).
[ Chemical 2 ]
[0006]
Here, R is hydrogen or an alkyl group having 1 to 5 carbon atoms, preferably an n-butyl group. Hydrogen bonded to carbon at the 4-position may be substituted with halogen such as chloro and bromo, alkyl groups having 1 to 12 carbon atoms or substituted alkyl groups.
Specific examples of raw materials include 5-hydroxymethylimidazole, 4-methyl-5-hydroxymethylimidazole, 2-methyl-5-hydroxymethylimidazole, 2-propyl-5-hydroxymethylimidazole, 2-butyl-5. -Hydroxymethylimidazole, 2-butyl-4-chloro-5-hydroxymethylimidazole and the like.
[0007]
In the present invention, it is an essential condition to use an alkaline water solvent in the catalytic oxidation reaction, and the use of such a solvent maintains the improvement in the yield of the target product.
Examples of the alkali in the alkaline water include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate and the like.
The amount of alkali used is 0.9 mol or more, preferably 1.0 to 1.5 mol, per mol of 5-hydroxymethylimidazole as a raw material. If it is less than 0.9 mol, the resulting 5-formylimidazoles will not dissolve in the system. On the other hand, when the amount exceeds 1.5 mol, the acid amount in the neutralization step increases, which is not practical.
[0008]
The noble metal catalyst used in the present invention is platinum, palladium, gold or the like, and platinum and palladium are practical. It is also possible to add bismuth, cerium, lead, indium or the like as the second component to such noble metal catalyst. Such a catalyst may be in the form of not only a metal state but also a salt, an oxide or the like. The noble metal catalyst used in the present invention is used as it is or supported on a carrier such as activated carbon, silica, alumina or the like as necessary.
In carrying out the catalytic oxidation reaction, an alkaline water solvent is charged into the reactor, and the above-mentioned catalyst and raw material 5-hydroxymethylimidazoles are supplied thereto.
[0009]
The means for charging all the chemicals used in the present invention is arbitrary, and batch charging, split charging, continuous charging, dropping charging, etc. can be carried out, but batch charging is particularly advantageous.
Various organic solvents can be used in combination as long as they do not depart from the spirit of the present invention.
[0010]
In the present invention, the amount of dissolved oxygen in the reaction liquid during the reaction is adjusted to 5 ppm or less, preferably 0 to 3 ppm, particularly preferably 0 to 2 ppm. Can be manufactured efficiently.
When the amount of dissolved oxygen exceeds 5 ppm, the yield of the target product decreases.
As a method for controls to 5ppm or less amount of dissolved oxygen in the reaction solution, not particularly limited, but it means the following is adopted.
1. The oxygen or air blowing speed is controlled. Usually, initial supply is performed at a rate of 0.01 to 1.0 milliliter (converted to the standard state) per minute per 1 g of 5-hydroxymethylimidazole, and the dissolved oxygen amount is reduced to 5 ppm or less thereafter. 1. Control the blowing speed so that 2. Use an inert gas such as helium, argon, nitrogen, carbon dioxide, or hydrogen, or a hydrocarbon such as methane, ethane, or propane to control the amount of oxygen. Additives that react with excess oxygen, such as methanol, ethanol, propanol, formaldehyde, acetaldehyde, propionaldehyde, etc., are added to the reaction solution for control.
In the present invention, if the stirring efficiency of the system is specified during the reaction, the effect is further exerted, and the P _V value is 0.3 or more, preferably 0.6 or more, particularly preferably 1.0 or more.
Here, the P _V value means the power required for stirring per unit volume of fluid, and is defined as stirring power (kW) of the stirrer / volume of reaction liquid (m ³ ).
If the P _V value is less than 0.3, the reaction does not proceed sufficiently, requiring a long time for the reaction, and increasing the production of by-products. On the other hand, even if the P _V value is too high, the effect of the present invention is not exhibited so much. Rather, the economic efficiency such as the need for a large stirrer is impaired, so the upper limit of the P _V value is 3.0, preferably 2.0. Is enough.
The type of the stirrer is not specified, and examples thereof include arbitrary ones such as a three-blade swept blade, a full zone blade, a turbine blade, and a max blend blade.
[0012]
The catalyst is used in an amount of 0.01 to 50 mol%, preferably 0.05 to 20 mol%, based on the starting 5-hydroxymethylimidazoles, but the effects of the present invention are remarkably exhibited. Is a range where the amount of catalyst used is small, that is, 0.1 to 10 mol%.
The solvent is used 3 to 50 times by weight of the raw material. If necessary, other organic solvents such as lower alcohols such as methanol, ethanol and propanol can be used in combination.
The reaction temperature may be any of 0 ° C. to reflux temperature, but is usually room temperature or higher, preferably 10 to 80 ° C., particularly preferably 15 to 60 ° C., and the reaction time is 1 to 24 hours, preferably 2 ~ 15 hours is advantageous.
[0013]
In the catalytic oxidation reaction, it is necessary to introduce oxygen or air into the above system. Of course, as described above, the dissolved oxygen in the reaction solution is controlled. The system may be atmospheric or pressurized. The reaction proceeds in a suspension system and is terminated when the absorption of oxygen is stopped, and the catalyst is filtered off from the reaction completed solution. Since 5-formylimidazoles are dissolved in the filtrate in the form of a salt, they are neutralized with a mineral acid such as sulfuric acid or hydrochloric acid to obtain crystals of the desired 5-formylimidazoles. Further purification is performed if necessary. The yield of the target product is 90% or more based on the starting 5-hydroxymethylimidazoles.
[0014]
【Example】
Hereinafter, the present invention will be described in detail with examples. “%” Is based on weight.
Example 1
100 g of 2-n-butyl-4-chloro-5-hydroxymethylimidazole was attached to a reactor equipped with a separable flask having an inner diameter of 100 mmφ and a turbine blade (blade diameter 60 mmφ), an oxygen gas blowing tube, a dissolved oxygen meter and a thermometer. (0.53 mol), 25.4 g (0.64 mol) of sodium hydroxide, 930 ml of water, and further a platinum-bismuth catalyst (activated carbon loaded with 5% platinum and 2% bismuth, water content 50%) Each 7g was charged.
While stirring so that the P _V value becomes 1.3, while controlling the temperature of the reaction solution at 20 ° C., oxygen is started to be blown at a rate of 20 ml / min, and the amount of dissolved oxygen in the reaction solution is kept at 2 ppm or less. A catalytic oxidation reaction was carried out for 8 hours.
[0015]
After completion of the reaction, the catalyst was filtered off from the reaction solution, and the filtrate was neutralized with 30% aqueous sulfuric acid to precipitate 2-n-butyl-4-chloro-5-formylimidazole as crystals, collected by filtration, and dried to obtain 95.1 g. Of white crystals were obtained.
The yield based on 2-n-butyl-4-chloro-5-hydroxymethylimidazole was 96.2%, and the purity was 100%.
As a result of infrared analysis and NMR analysis, it could be confirmed as 2-n-butyl-4-chloro-5-formylimidazole.
[0016]
Example 2
Reduce the amount of catalyst to 5g in Example 1, a stirring blade in a full zone blade, except for changing the P _V value of 1.8 was experimentally according the example.
However, nitrogen was blown in from about 8 hours, and the amount of dissolved oxygen was set to 2 ppm or less, and the reaction was carried out for 10 hours.
2-n-butyl-4-chloro-5-formylimidazole (purity 100%) was obtained with a yield of 97.0%.
[0017]
Example 3
In Example 1, an experiment was performed according to the same example except that a Max blend blade was used as a stirring blade, the P _V value was changed to 1.5, the reaction temperature was changed to 40 ° C., and the initial oxygen blowing was changed to 80 ml / min. . The amount of dissolved oxygen during the reaction was 3 pm or less.
2-n-butyl-4-chloro-5-formylimidazole (purity 100%) was obtained with a yield of 95.1%.
[0018]
Example 4
In Example 1, the catalytic oxidation reaction was carried out by changing the catalyst to 3.3 g of platinum black and the reaction temperature to 60 ° C. The amount of dissolved oxygen during the reaction was 2 ppm or less.
As a result of infrared analysis and NMR analysis, it could be confirmed as 2-n-butyl-4-chloro-5-formylimidazole. The purity was 100% and the yield was 94.0%.
[0019]
Example 5
According to Example 1, 2-n-butyl-5-hydroxymethylimidazole was catalytically oxidized. The amount of dissolved oxygen during the reaction was 2 ppm or less.
As a result of infrared analysis and NMR analysis, it could be confirmed as 2-n-butyl-5-formylimidazole. The purity was 100% and the yield was 93.0%.
[0020]
Example 6
According to Example 1, the catalytic oxidation reaction of 4-methyl-5-hydroxymethylimidazole was performed. The amount of dissolved oxygen during the reaction was 2 ppm or less.
As a result of infrared analysis and NMR analysis, 4-methyl-5-formylimidazole was confirmed. The purity was 100% and the yield was 92.0%.
[0021]
Example 7
According to Example 1, the catalytic oxidation reaction of 5-hydroxymethylimidazole was performed. The amount of dissolved oxygen during the reaction was 2 ppm or less.
As a result of infrared analysis and NMR analysis, it was confirmed as 5-formylimidazole.
The purity was 100% and the yield was 91.5%.
[0022]
Control Example 1
When the amount of dissolved oxygen was 5 ppm or more in Example 1, the experiment was conducted as it was, and 2-n-butyl-4-chloro-5-formylimidazole (purity 82.6%) was obtained in a yield of 77.3%. I just got it.
[0023]
【The invention's effect】
The present invention uses an alkaline water solvent to produce 5-formylimidazoles such as 2-alkyl-5-formylimidazole useful as a raw material for pharmaceuticals such as diuretics and antihypertensive agents by a catalytic oxidation method. When the reaction is carried out while maintaining the dissolved oxygen content in the liquid at 5 ppm or less, the target product can be obtained in a high yield even if the amount of noble metal catalyst used is reduced, which is very advantageous in terms of economy and production. .

Claims (2)

In an alkaline water solvent, 5-hydroxymethylimidazoles represented by the following general formula (1) are catalytically oxidized by introducing oxygen or air in the presence of a noble metal catalyst, and represented by the following general formula (2). -A process for producing 5-formylimidazoles, wherein the reaction is carried out while maintaining the amount of dissolved oxygen in the reaction solution at 5 ppm or less in producing formylimidazoles.
(In the formula, R is hydrogen or an alkyl group having 1 to 5 carbon atoms, and hydrogen bonded to carbon at the 4-position may be substituted with halogen, an alkyl group having 1 to 12 carbon atoms or a substituted alkyl group. .)   2. The production method according to claim 1, wherein a platinum or palladium-based catalyst is used as the noble metal catalyst.