JP2001002655A - Production of 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a high-purity 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative in good yield according to an industrially simple method. SOLUTION: A 2-alkyl-5-hydroxymethylimodazole derivative is reacted with N-chlorosuccinimide in an organic solvent to provide a reactional liquid containing the resultant 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative. The obtained reactional liquid is then mixed in a mixed solvent of a water- insoluble organic solvent with an acidic aqueous solution to extract the 2-alkyl-4- chloro-5-hydroxymethylimidazole derivative into the acidic aqueous solution. The extracted solution is subsequently collected by separation and then regulated to pH 4.5-9.0 with an alkali to deposit a crystal and an organic solvent in an amount of 0.6-1.4 times based on water present in the system is added to dissolve the crystal, which is subsequently redeposited and separated by filtration.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to 2-alkyl-4-alkyl-4-alkyl-4-alkyl-4-alkyl-4- [pi] yl.
The present invention relates to a method for producing a chloro-5-hydroxymethylimidazole derivative.

[0002]

2. Description of the Related Art 2-Alkyl-4-chloro-5-hydroxymethylimidazole derivatives are important as pharmaceutical intermediates, and there are several reports on their production.
For example, a method of reacting a substituted imidazole with N-halosuccinimide in a polar solvent such as dioxane or 2-methoxyethanol (JP-A-63-23868).
JP-A-5-239053), a method of reacting 2-butylimidazole-4-methanol with N-chlorosuccinimide in ethyl acetate, and chlorinating a 5-hydroxymethylimidazole derivative to obtain 4
A method for obtaining a -chloro-5-hydroxymethylimidazole derivative (Japanese Patent Application Laid-Open No. Hei 7-118239) has been proposed. Among them, methods in terms of quality and yield are considered to be advantageous as industrial production methods.

[0003] However, in this method, a by-product, 2-alkyl-4,5-dichloroimidazole derivative (hereinafter abbreviated as dichloro form) is considerably produced, and even in the disclosed technique, the pH of the aqueous solution of the reaction mixture is reduced. A purification method has been disclosed in which the dichloride is removed by precipitation by adjusting the amount of the dichloride. However, in this method, it is necessary to obtain the target substance from the mother liquor.
There was a problem that the cost of the -alkyl-4-chloro-5-hydroxymethylimidazole derivative was increased.

In order to solve the above-mentioned problem, the applicant of the present invention disclosed in Japanese Unexamined Patent Publication No. Hei 9-176129 a 2-alkyl-5-hydroxymethylimidazole derivative and an N-
A reaction product containing a 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative obtained by reacting chlorosuccinimide with an organic solvent is mixed in a mixed solvent of a water-insoluble organic solvent and an acidic aqueous solution, The by-products are extracted into the organic solvent layer, while the 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative is extracted into the acidic aqueous solution, and the separated acidic aqueous extract is neutralized once. It also discloses that by filtering and recrystallizing with an organic solvent or water, a 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative with high yield and high purity can be obtained. That is, in this technique, the intended purpose was achieved by changing the conventional pH adjustment method to a solvent extraction method as a means for purifying by-products.

[0005]

However, in the method disclosed in JP-A-9-176129, a 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative can be obtained with high purity and high yield. It is necessary to neutralize the acidic aqueous solution of the extracted 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative once to precipitate crystals, which need to be separated by filtration. I was forced to.

[0006]

The present inventors have conducted intensive studies based on the finding that it would be industrially advantageous to omit such a filtration operation. As a result, the present inventors have found that 2-alkyl-5-hydroxymethylimidazole derivatives and A reaction product containing a 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative obtained by reacting N-chlorosuccinimide with a water-insoluble organic solvent is mixed with a water-insoluble organic solvent and an acidic aqueous solution. In 2-alkyl-4-
After extracting the chloro-5-hydroxymethylimidazole derivative into an acidic aqueous solution, the extract is separated and the extract is further adjusted to pH 4.5 to 9.0 with alkali to precipitate crystals. After that, the organic solvent is immediately added to the water present in the system in an amount of 0.6 to 1.4 without performing the filtration operation.
After dissolving the crystals by adding twice the weight and reprecipitating the crystals again, the inventors have found that a high-purity 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative can be obtained in high yield and the present invention. Was completed.

Although at the time of the filing application it was expected that the presence of a large amount of water at the time of crystallization would reduce the yield, such a phenomenon was surprisingly limited only to a certain amount of water increase. On the contrary, in the case of a region in which the amount of water considerably exceeds a certain amount, the yield is not significantly reduced, and a great advantage that the filtration operation in purification can be omitted can be obtained. Considering
A major feature of the present invention is that it can be said that it is more advantageous from an overall point of view when implemented on an industrial scale.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. The 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative of the present invention is obtained by the following reaction formula, and its production reaction step will be described in detail.

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The alkyl group of the 2-alkyl-5-hydroxymethylimidazole derivative is a derivative substituted with an alkyl group such as methyl group, ethyl group, propyl group, n-butyl group, t-butyl group and other functional groups. Alternatively, it is possible to produce the desired 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative correspondingly.

The amount of N-chlorosuccinimide used is 2-
Alkyl-5-hydroxymethylimidazole derivative 1
0.9 to 2.0 moles, preferably 0.95 moles per mole
~ 1.5 mol is suitable. If the amount is less than 0.9 mol, the reaction does not proceed sufficiently, and the 2-alkyl-5-hydroxymethylimidazole derivative remains. If the amount exceeds 2.0 mol, a large amount of dichloro form is formed and 2-alkyl-4-chloro- 5
The yield of the hydroxymethylimidazole derivative is reduced.

The above reaction is carried out in an organic solvent. Examples of such an organic solvent include hydrophilic solvents such as acetone, methanol and ethanol, methyl chloride, methylene chloride, chloroform, carbon tetrachloride, 1-chloroethane, −
Halogenated hydrocarbons such as dichloroethane, saturated hydrocarbons such as pentane, hexane, heptane and octane; aromatic hydrocarbons such as benzene, toluene and xylene; esters such as ethyl acetate and isopropyl acetate; ketones such as methyl isobutyl ketone; Ethers such as ethyl ether, propyl ether and t-butyl methyl ether alone,
Or two or more kinds are used in combination,
-Dichloroethane, hexane, toluene, ethyl acetate,
Water-insoluble organic solvents such as methyl isobutyl ketone and t-butyl methyl ether are used alone or in combination of two or more.

The amount of the solvent used is not particularly limited as long as the reaction system is a slurry system or a solution system and can be stirred, but it is 10 to 30 times the molar amount of the 2-alkyl-5-hydroxymethylimidazole derivative. , Preferably 13 to
It is used in a 27-fold molar range. If the molar ratio is less than 10 times, the yield of the 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative tends to decrease.
If the molar ratio exceeds twice, the yield will not be improved, and the production efficiency will be reduced, which is not preferable.

In the above reaction, when an alkali coexists, 2
-The yield of the alkyl-4-chloro-5-hydroxymethylimidazole derivative is improved. The alkali used at that time, for example, sodium hydrogen carbonate, sodium carbonate, inorganic salts such as potassium hydrogen carbonate, triethylamine,
Examples include amines such as pyridine. The amount of the alkali to be used is appropriately 0.05 to 1.5 times, preferably 0.2 to 1.0 times the mol of the 2-alkyl-5-hydroxymethylimidazole derivative. When the amount of the alkali is 0.05 mol or less, the yield of the 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative decreases.

The means for charging all the drugs used above is optional, and any of batch charging, divided charging, continuous charging, dropping charging and the like can be performed. Usually, first, a 2-alkyl-5-hydroxymethylimidazole derivative and an alkali are charged in a solvent, and then N-chlorosuccinimide is added at 0 to 30 ° C, preferably at 5 to 20 ° C.
Charge in 10 hours. The form of the drug may be a powder, or a solution or slurry. Reaction temperature is 0-3
0 ° C., preferably at 5-20 ° C., for 15 minutes to 5.0 hours,
It is preferably aged for 30 minutes to 3.0 hours. By such a reaction, a reaction product containing a 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative is obtained.

Next, the desired product is obtained by purifying the reaction product. In the purification, a water-insoluble organic solvent is added to the reaction product.If the organic solvent used in the reaction is a water-insoluble organic solvent, the water-insoluble organic solvent may not be distilled off, and in some cases, the water-insoluble organic solvent may not be distilled off. May be appropriately added.
When the organic solvent used in the reaction is a water-soluble organic solvent, the water-soluble organic solvent is removed from the reaction system by distillation under reduced pressure or the like, and then a water-insoluble organic solvent is added.

Examples of the water-insoluble organic solvent include halogenated hydrocarbons such as methyl chloride, methylene chloride, chloroform, carbon tetrachloride, 1-chloroethane and 1,2-dichloroethane, saturated hydrocarbons such as pentane, hexane, heptane and octane; Benzene, toluene, aromatic hydrocarbons such as xylene, ethyl acetate, esters such as isopropyl acetate,
Ketones such as methyl isobutyl ketone, ethers such as ethyl ether, propyl ether, t-butyl methyl ether and the like are used alone or in combination of two or more. Preferably, 1,2-dichloroethane, hexane, ethyl acetate , Methyl isobutyl ketone, t-butyl methyl ether and the like are used alone or in combination of two or more.

The amount of the water-insoluble organic solvent at the time of purification is 2
It is 10 to 30 moles, preferably 13 to 27 moles, based on the -alkyl-5-hydroxymethylimidazole derivative. Further, a 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative is extracted into the aqueous solution in the presence of an acidic aqueous solution. Acids used for preparing the acidic aqueous solution include hydrochloric acid, sulfuric acid and the like.

Further, the amount of the acid is 1.0 to 2.0 based on the 2-alkyl-5-hydroxymethylimidazole derivative.
A 0-fold molar amount, preferably 1.1-1.8-fold molar amount is used. When the amount of the acid is less than 1.0 mole, 2-alkyl-4-
The chloro-5-hydroxymethylimidazole derivative is not sufficiently extracted, which is not preferable. If the chloro-5-hydroxymethylimidazole derivative is more than 2.0 moles, even impurities such as dichloro form are undesirably extracted into the acidic aqueous solution. The concentration of the acidic aqueous solution is 1 to 30% by weight, preferably 3 to 20% by weight. If the acid concentration is less than 1% by weight, a large amount of acidic aqueous solution is required at the time of extraction, and the extraction efficiency is not practical. Conversely, if it exceeds 30% by weight, various impurities are generated, which is not preferable.

After coexisting with the acidic aqueous solution, the mixture is usually stirred at room temperature (20 ° C.) for about 15 minutes. Thereafter, the mixture is allowed to stand to separate into two layers, and liquid separation is performed to take out an aqueous layer portion. Since the pH of the aqueous layer is 0.1 to 1.5, the pH is adjusted to 4.
5 to 9.0, preferably 5.5 to 7.5. pH
Is less than 4.5, the yield of the 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative decreases,
Exceeds 9.0, the purity of the obtained 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative is undesirably reduced.

Examples of the alkali used in the above include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate and the like. Sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate Is preferred. By adjusting the pH to the above value, 2-alkyl-4-chloro-
Although crystals of the 5-hydroxymethylimidazole derivative precipitate, the present invention is characterized in that an organic solvent is added to the system without filtering the crystals. The organic solvent is not particularly limited, but acetone, methanol, ethyl acetate, toluene, methyl isobutyl ketone, ethylene dichloride, t
-Butyl methyl ether and the like, and preferably, ethyl acetate, methyl isobutyl ketone, t-butyl methyl ether and the like.

With respect to the amount of the organic solvent, it is necessary to add 0.6 to 1.4 times by weight, preferably 0.7 to 1.3 times by weight of the organic water. If the amount of the organic solvent is less than 0.6 times the weight, no effect of improving the purity is obtained. On the other hand, if the weight exceeds 1.4 times, the yield is undesirably reduced. When an organic solvent is added, the slurry system is an organic solvent / water slurry system, which is heated to completely dissolve the crystals in the slurry.

Thereafter, the temperature is 20 ° C. or less, preferably 0 to 15 ° C.
Cooling while stirring until crystallization occurs. The solubility in organic solvents is 2-alkyl-4-chloro-5-
Since the hydroxymethylimidazole derivative is lower than by-products such as the dichloride, a highly pure 2-alkyl-
The 4-chloro-5-hydroxymethylimidazole derivative can be obtained efficiently.

The obtained crystals are filtered off by any means such as centrifugation, and the obtained wet cake is washed with an organic solvent or water, and 2-alkyl-4-chloro-99-100% pure.
The 5-hydroxymethylimidazole derivative was obtained in a yield of 65-65.
Obtain at 87%. The thus obtained 2-alkyl-4-chloro-5-hydroxymethylimidazole derivatives are very useful as intermediates for pharmaceuticals such as angiotensin II antagonists and cardiovascular drugs.

[0024]

The present invention will be specifically described below with reference to examples. In Examples, “%” is based on weight unless otherwise specified. Example 1 2-butyl-5-hydroxymethylimidazole77.
1 g (0.5 mol), sodium bicarbonate 21.0 g
(0.25 mol) to 840 g (9.5 mol) of ethyl acetate
To prepare a slurry liquid. While maintaining the internal temperature of the slurry at 20 ° C. or lower, N-chlorosuccinimide 7
3.4 g (0.55 mol) were separately charged in 3 hours (internal temperature 10 to 15 ° C.). After completion of the addition of N-chlorosuccinimide, the mixture was aged for 2 hours (internal temperature: 10 to 15 ° C).

Next, 1.1% mol of 10% hydrochloric acid with respect to 2-butyl-5-hydroxymethylimidazole 200.
8 g (0.55 mol) was added, and the imidazole was extracted into the aqueous layer. Separate the aqueous layer while adding 10 mL to the ethyl acetate layer.
% Hydrochloric acid (54.8 g, 0.15 mol) was added, and the mixture was extracted again to collect an aqueous layer. Mixing the recovery layer with the aqueous layer,
The pH was adjusted to 6.5 with a 25% aqueous sodium hydroxide solution to precipitate crystals of 2-butyl-4-chloro-5-hydroxymethylimidazole. Then, 250 g of ethyl acetate (corresponding to 0.88 times the weight of the system water) was added to the aqueous layer, and the mixture was stirred at 62 ° C. to dissolve the crystals. After the crystals were completely dissolved, the mixture was cooled to 10 ° C with stirring for 1 hour,
Crystals of butyl-4-chloro-5-hydroxymethylimidazole were precipitated again. The obtained crystals are filtered and filtered.
C. for 4 hours under vacuum.
74.5 g of hydroxymethylimidazole (purity 100
%, Yield 79.0%).

EXAMPLE 2 Instead of 77.1 g (0.5 mol) of 2-butyl-5-hydroxymethylimidazole of Example 1, 2-ethyl-
63.1 g of 5-hydroxymethylimidazole (0.5
Mol)), the same experiment was carried out, and 2-ethyl-
4-Chloro-5-hydroxymethylimidazole was obtained with a yield of 60.4% and a purity of 99.9%.

Example 3 In place of 77.1 g (0.5 mol) of 2-butyl-5-hydroxymethylimidazole in Example 1, 63.1 g of 2-hexyl-5-hydroxymethylimidazole (0.5 mol) was used.
5 mol) was used, and the same experiment was performed.
% 2-hexyl-4-chloro-5-hydroxymethylimidazole was obtained in a yield of 67.5%.

Example 4 Ethyl acetate 25 added to the pH 6.5 adjusting solution in Example 1
An experiment was conducted in the same manner except that 350 g of methyl isobutyl ketone (corresponding to 1.23 times the weight of water in the reaction system) was used instead of 0 g. Hydroxymethylimidazole was obtained in a yield of 77.5%.

Example 5 Ethyl acetate 25 added to the pH 6.5 adjusting solution in Example 1
An experiment was conducted in the same manner except that 210 g of t-butyl methyl ether (corresponding to 0.74 times the weight of water in the reaction system) was used instead of 0 g. 5-Hydroxymethylimidazole was obtained in a yield of 77.4%.

Example 6 2-butyl-5-hydroxymethylimidazole 77.
1 g (0.5 mol), sodium bicarbonate 21.0 g
(0.25 mol) in 660 g of t-butyl methyl ether
(7.5 mol) to obtain a slurry liquid. While maintaining the internal temperature of the slurry at 20 ° C. or lower, 73.4 g (0.55 mol) of N-chlorosuccinimide was separately charged in 3 hours (internal temperature 10 to 15 ° C.). After completion of the addition of N-chlorosuccinimide, the mixture was aged for 2 hours (internal temperature 10 to 15).
° C). The reaction solution was concentrated to dryness to obtain a reaction product.

Next, 750 g (7.5 mol) of methyl isobutyl ketone was added to 160.9 g of the obtained reaction product.
Furthermore, 200.8 g (0.5%) of 10% hydrochloric acid, which is 1.1 times the molar amount of 2-butyl-5-hydroxymethylimidazole.
5 mol), and the imidazole was extracted into the aqueous layer. Separate the aqueous layer while adding 1 to the methyl isobutyl ketone layer.
54.8 g (0.15 mol) of 0% hydrochloric acid was added, and the mixture was extracted again to collect an aqueous layer. The recovered layer was mixed with the aqueous layer, and the pH was adjusted to 6.5 with a 25% aqueous sodium hydroxide solution to precipitate crystals of 2-butyl-4-chloro-5-hydroxymethylimidazole. Next, 250 g of ethyl acetate (corresponding to 0.88 times the weight of the system water) was added to the aqueous layer, and the mixture was stirred at 62 ° C. to dissolve the crystals. After the crystals were completely dissolved, the mixture was cooled to 10 ° C with stirring for 1 hour,
Crystals of butyl-4-chloro-5-hydroxymethylimidazole were precipitated again. The obtained crystals are filtered and filtered.
C. for 4 hours under vacuum.
74.0 g of hydroxymethylimidazole (purity 100
%, Yield 78.5%).

COMPARATIVE EXAMPLE 1 Ethyl acetate 25 added to the pH 6.5 adjusting solution in Example 1.
The same experiment was carried out except that the amount of 0 g was changed to 455 g (corresponding to 1.6 times the weight of the water in the reaction system). As a result, 2-butyl-4-chloro-5-hydroxy having a purity of 99.9% was obtained. Methyl imidazole was obtained in a yield of 61.0%.

Comparative Example 2 Ethyl acetate 25 added to the pH 6.5 adjusting solution in Example 1
The same experiment was conducted except that the amount of 0 g was changed to 115 g (corresponding to 0.4 times the weight of the water in the reaction system).
-Butyl-4-chloro-5-hydroxymethylimidazole was obtained with a purity of 89.0% and a yield of 70.0%.

[0034]

According to the present invention, there is provided a 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative obtained by reacting a 2-alkyl-5-hydroxymethylimidazole derivative with N-chlorosuccinimide in an organic solvent. Is mixed in a mixed solvent of a water-insoluble organic solvent and an acidic aqueous solution, and the 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative is extracted into the acidic aqueous solution. And further precipitate crystals, and then the organic solvent is added to water present in the system.
By dissolving the crystals by adding 0.6 to 1.4 times the weight and then re-precipitating the crystals, a high-purity 2-alkyl-containing almost no by-product dichloride is mixed.
The 4-chloro-5-hydroxymethylimidazole derivative can be obtained in good yield.

Claims (1)

[Claims] 1. A reaction product containing a 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative obtained by reacting a 2-alkyl-5-hydroxymethylimidazole derivative with N-chlorosuccinimide in an organic solvent. The product was mixed in a mixed solvent of a water-insoluble organic solvent and an acidic aqueous solution, and the 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative was extracted into the acidic aqueous solution. Extract pH with alkali
Was adjusted to 4.5 to 9.0 to precipitate crystals, and then the organic solvent was added to water in the system in an amount of 0.6 to 1.4 times by weight to dissolve the crystals. A method for producing a 2-alkyl-4-chloro-5-hydroxymethylimidazole derivative, comprising: