JPS63301869A - Production of 2-aminoimidazole or salt thereof - Google Patents

Abstract

PURPOSE:To obtain the titled compound by easy process operation in high yield, industrially and advantageously, by reacting an aminoacetylaldehyde dialkyl acetal with an aqueous salt of S-methylisothiourea and then subjecting the reaction product to ring formation reaction with a specific amount of a strong acid. CONSTITUTION:An aminoacetylaldehyde dialkyl acetal shown by formula I is reacted with an aqueous salt of S-methylisothiourea such as sulfate in a water medium at reflux temperature for 1-3hr to form an N-(2,2-dialkoxyethyl) guanidine salt shown by formula III (first process), preferably not isolated, 1mol. of the reaction product is subjected to ring formation reaction in the presence of 0.005-0.5 equivalent strong acid such as sulfuric acid or hydrochloride acid at reflux temperature for 1-3hr (second process) to give the aimed compound shown by formula IV useful as an intermediate for drugs. Since the reactions including isolating and purifying process can be carried out only in the aqueous system throughout the first and the second processes, this method has merits of no danger in handling organic solvents.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a method for producing 2-7minoimidazole or its salt in high yield from aminoacetaldehyde dialkyl acecool and S-methylisothiourea aqueous salt. be.

BACKGROUND OF THE INVENTION 2-Aminoimidazole or its salts are useful as pharmaceutical intermediates.

B, T, 5torey et al, J, O
rg, Chew, 29°3118 (1964)
contains aminoacetaldehyde diethyl acetal and S
A method for obtaining 2-aminoimidazole sulfate by a two-step reaction involving reaction with -methylisothiourea sulfate and subsequent heating with concentrated hydrochloric acid is shown.

Specifically, in the first step, 25 g (0,187 mol) of aminoacetaldehyde diethylacetal
and S-methylisothiourea sulfate 25g (0,180
N-(2,2-jethoxyethyl) is reacted with heat in an aqueous medium, and after the reaction, water is removed to obtain an oily substance, which is dissolved in methanol and then precipitated with acetone. Guanidine sulfate 31 g (0,13
8 mol). The yield based on S-methylisothiourea sulfate is 77%.

Next, in the second step, 10 g of N-(2,2-jethoxyethyl)guanidine sulfate obtained above (0,04
5 mol) to 6 ml of concentrated hydrochloric acid (0.051 as a 30% concentration)
37 mol, 0.0789 mol as 39% strength), water is added, the solution is evaporated to a syrup, water is added and the solution is evaporated again, the syrup is dissolved in absolute ethanol, anhydrous Precipitation with ether yielded 2.3 g of the desired product, 2-aminoimidazole sulfate. Yield is 38%.

The amount of concentrated hydrochloric acid used in the second step is 1.7 per mole of N-(2,2-jethoxyethyl)guanidine sulfate.
(in the case of concentrated hydrochloric acid with a concentration of 39%) to 1.3 (in the case of concentrated hydrochloric acid with a concentration of 30%).

The yield of 2-aminoimidazole sulfate through the first and second steps is 0.77 x O, 39 x 100 = 3 based on the starting material S-methylisothiourea sulfate.
It becomes 0%.

Problems to be Solved by the Invention According to the above-mentioned conventional method, the yield of 2-aminoimidazole sulfate through the first and second steps is 30% based on the starting material S-methylisothiourea sulfate. %, and it is necessary to significantly improve the yield for industrialization.

Further, in the above-mentioned conventional method, there are problems in that the operations for isolating the intermediate product in the first step and the final product in the second step are complicated and that an organic solvent must be used.

The present invention aims to find an industrially advantageous method for obtaining 2-aminoimidazole or its salt in high yield from aminoacetaldehyde dialkyl acetal and S-methylisothiourea aqueous salt by improving the conventional method described above. It has been done.

Means for Solving the Problems The method for producing 2-aminoimidazole or a salt thereof of the present invention comprises aminoacetaldehyde dialkyl acetal and S
- A first step of reacting the aqueous salt of methylisothiourea in an aqueous medium to obtain an N-(2,2-dialkoxyethyl)guanidine salt, and the produced N-(2,2-dialkoxyethyl)guanidine. In carrying out the second step of manufacturing 2-aminoimidazole or its salt by cyclizing the salt in the presence of a strong acid, the cyclization reaction in the second step is performed using N-(2,2-dialkoxyethyl ) It is characterized in that it is carried out in the presence of 0.05 to 0.5 h% of a strong acid per mole of guanidine salt.

The present invention will be explained in detail below.

First step> The first step of the present invention is a step of reacting an aminoacetaldehyde dialkyl acetal with an aqueous S-methylisothiourea salt in an aqueous medium to obtain an N-(2,2-dialkoxyethyl)guanidine salt. Consisting of

Examples of the alkyl group in the aminoacetaldehyde dialkyl acetal include lower alkyl groups such as methyl, ethyl, propyl, and butyl. Since this alkyl group is eventually removed, methyl or ethyl groups are industrially advantageous.

As the aqueous salt of S-methylisothiourea, sulfate, hydrochloride, etc. are used.

Since the reaction between the aminoacetaldehyde dialkyl acetal and the aqueous S-methylisothiourea salt in the first step is an equimolar reaction, both are used in approximately proportions corresponding to the reaction. However, from cost considerations, it is more advantageous to use the latter a little more than the former. Usually, 0.9 to 1.3 mol of aminoacetaldehyde dialkyl acetal is added per mol of S-methylisothiourea aqueous salt, especially 1N.
1.1 mol is used.

The amount of water as a medium is often 5 to 20 times the molar amount of aminoacetaldehyde dialkyl acecul (or S-methylisothiourea aqueous salt).

The reaction temperature is selected from the range of 30°C to reflux temperature, and the reaction is usually carried out at reflux temperature.

The reaction time is about 1 to 3 hours when the reaction is carried out at reflux temperature.

There is no particular limitation on the method of feeding the raw materials, and both a batch feeding method and a method of sequentially adding one aqueous liquid (aqueous solution or aqueous dispersion) to the other aqueous liquid are employed.

<Second step> In the second step, the N-(2,2-dialkoxyethyl)guanidine salt produced in the first step is subjected to a cyclization reaction in the presence of a strong acid to produce 2-aminoimidazole or its salt. Consists of processes.

Then, the cyclization reaction in this second step is carried out with N-(2,2
-dialkoxyethyl)guanidine salt in the presence of 0.05 to 0.5 equivalents of strong acid per mole of the guanidine salt.

The reaction in the second step involves the N-(2,2-
Although it is possible to carry out the step after once isolating the (dialkoxyethyl)guanidine salt, the yield is better and the operation is easier if the second step is carried out without isolating it.

As the strong acid, sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, trichloroacetic acid, etc. are used.

As mentioned above, the amount of strong acid used is 0.05 to 0 per mole of N-(2,2-dialkoxyethyl)guanidine salt.
, 5 equivalents, preferably 0.1 to 0.4 equivalents.
If the amount is less than 0.05 equivalent, the yield of 2-7 minoimidazole salt will decrease, while if it exceeds 0.5 equivalent, the yield of 2-7 minoimidazole salt will decrease.
The yield of aminoimidazole salt decreases.

The amount of water in the system is usually 10 to 100 moles per mole of S-methylisothiourea aqueous salt when the first step and the second step are performed successively.

The reaction temperature is selected from the range of 30°C to reflux temperature, and the reaction is usually carried out at reflux temperature.

The reaction time is about 1 to 3 hours when the reaction is carried out at reflux temperature.

Regarding the reaction temperature and time, it is sufficient to carry out the reaction at reflux temperature for about 2 hours, for example.

After the reaction, the reaction solution is concentrated and, if necessary, cooled to crystallize the target 2-aminoimidazole salt. It is preferable to use water as the cleaning liquid and not to use organic solvents. The dissolved target substance is also recovered from the filtrate and washing liquid by the same means.

For production The reaction in the first step of the present invention is represented by the following formula.

OR5CH) H,N　NH ＼〃 The reaction in the second step is represented by the following formula.

In the present invention, the yield in the second step is improved by using an appropriate amount of strong acid in the second step. In particular, if the first step and the second step are performed successively, the yield is further improved and the process operation is simplified.

Example Next, the present invention will be further explained with reference to Examples.

Example 1 <Step 1> Into a round bottom flask equipped with a reflux condenser, a dropping funnel, a thermometer, and a stirrer, 192 g of an aqueous solution of aminoacetaldehyde dimethyl acetal (containing 34.4 g of water, so 1.5 mol net) was added. In addition, 200.45 g (1.44 mol) of S-methylisothiourea sulfate and 3 mol of water were added.
A mixed solution (slurry) of No. 001 was added at room temperature with stirring, and the temperature was slowly raised to reflux temperature after about 1 hour, followed by refluxing for 1.5 hours.

During reflux, 6.20 g of S-methylisothiourea sulfate
(0,045 mol) was additionally charged. During the temperature rise, the system slowly changed from a slurry to a colorless homogeneous system, and methyl mercaptan was generated, and this generation continued for 1 hour after the start of the temperature rise.

After the reaction is completed, the temperature is reduced to 11% under reduced pressure using a water aspirator.
It was concentrated at 0°C to obtain a pale brown viscous liquid with a weight of 333°Og.

In analysis by liquid chromatography, N-(2,2
The yield of guanidine salt (-dimethoxyethyl) was 30%, and the production of 2-7 minoimidazole corresponding to a yield of 3% was also observed.

<Second step> Subsequently, add 1450 ml of water and 2 ml of 62.4% sulfuric acid to this liquid.
5.2 g (o, te mol) (i.e. N-(2,2
-dimei xyethyl) 0 per mole of guanidine salt
, 24 equivalents were added and refluxed for 2 hours.

Add 75% bath salt to the reaction solution using a rotary evaporator.
The mixture was concentrated under reduced pressure with a water aspirator at °C until bumping, yielding 261 g of a dark brown thick slurry. This slurry liquid is suction-filtered at 40 to 60°C, and the filtered mass is collected at a water temperature of 27°C.
was washed with 53 ml of water. By drying this,
118.0 g (0.89 mol) of light brown 2-aminoimidazole sulfate prismatic crystals were obtained. The crystals decomposed at 270°C as determined by melting point measurements.

On the other hand, the filtrate and the water washing solution were combined and concentrated, and the same procedure was performed to obtain 33.8 g (0.28 mol) of light brown prismatic crystals of 2-aminoimidazole sulfate. The crystals decomposed at 285°C as determined by melting point measurements.

The yield of 2-aminoimidazole sulfate through the first and second steps is 100X (0,89+0.28)/(1,4
4+0.045) = 77.4%.

Comparative Example 1: The amount of 62.4% sulfuric acid added in the 52nd step was 126
The second step of Example 1 was repeated, except that 0.8 mol of N-(2,2-dimethoxyethyl)guanidine salt was used (1.2 equivalents per 1 mol of N-(2,2-dimethoxyethyl)guanidine salt).

The reaction solution was concentrated, suction filtered, and the filtered mass was washed to obtain 45.1 g (0.34 mol) of light brown prismatic crystals of 2-aminoimidazole sulfate.

On the other hand, the filtrate and water washings were combined and concentrated, and the same operation was repeated, but no crystals were obtained.

The yield of 2-aminoimidazole sulfate through the first and second steps is 100X O,34/(1,44+0.045) based on S-methylisothiourea sulfate.
)=23%.

Example 2 <1st step> Aminoacetaldehyde dimethyl acetal aqueous solution 19
Example except that 223 g of aminoacetaldehyde diethyl acetal aqueous solution (containing 23.2 g of water, so 1.5 mol net) was used instead of 2 g (containing 34.4 g of water, so 1.5 mol net). The first step of Step 1 was turned green.

After the reaction is completed, the temperature is reduced to 11% under reduced pressure using a water aspirator.
It was concentrated at 0°C to obtain 368 g of a pale brown viscous liquid.

In analysis by liquid chromatography, N-(2,2
Estimated yield of -jethoxyethyl)guanidine salt is 82%
The production of 2-aminoimidazole corresponding to a yield of 2% was also observed.

(Second step) Next, add 145h+ of water and 36% concentrated hydrochloric acid leg to this solution.
(0.18 mol) (that is, 0.117 equivalents per 1 mol of N-(2,2-jethoxyethyl)guanidine salt) was added, and the second step of Example 1 was then repeated.

By concentrating the reaction solution, filtering it under suction, and washing the filtered mass, 121.2 g (0.92 mol) of light brown 2-
Prism crystals of aminoimidazole sulfate were obtained.

On the other hand, the filtrate and the water washing solution were combined and concentrated, and the same procedure was performed to obtain 25.6 g (0.19 mol) of pale dark brown prismatic crystals of 2-aminoimidazole sulfate.

The yield of 2-7 minoimidazole sulfate through the first and second steps was 74.8% based on S-methylisothiourea sulfate.

Comparative Example 2 The amount of 36% concentrated hydrochloric acid added in the second step was changed to 210 g (2
, 1 mole) (i.e., 1.521 iL per mole of N-(2,2-jethoxyethyl)guanidine salt), the second step of Example 2 was repeated, and 1 g of the syrupy concentrate 2Ei was added. However, no crystal precipitation was observed.

One liter of ethanol was added to the syrup, and the precipitated crystals were suction-filtered to obtain 52 g of crystals. Since the crystals did not show a clear melting point (decomposition temperature), they were purified by recrystallization in 40 ml of water to obtain 23.2 g (0.18 mol) of crystals (melting point 26
6°C1 decomposition) was obtained.

The yield of 2-aminoimidazole sulfate through the first and second steps was only 12% based on S-methylisothiourea sulfate.

Comparative Example 3 The first step of Example 2 was repeated, and the reaction solution after the first step was concentrated to obtain a viscous liquid. After dissolving this viscous liquid in methanol, add acetone to crystallize it, and filter it to obtain crystals 2.
36 g (1.05 mol, melting point 144-150°C) were obtained. The filtration performance was very poor, and the operation required a lot of effort.

The second step of Example 2 was repeated by adding 140 ml of 38% concentrated kM# and 1 ml of water to the above crystals, but no crystals were obtained and a syrupy fM condensate was obtained. 5901 ethanol was added to the syrup to form an ethanol solution (there was no undissolved material), ethyl ether was added to this solution to crystallize it, and 72.1 g of crystals (0.55 mol, melting point 264°C, decomposed) was obtained by filtration. I got it.

The filtration performance was very poor, and the operation required a lot of effort.

The yield of 2-aminoimidazole sulfate through the first and second steps was 36.8% based on S-methylisothiourea sulfate.

Effects of the Invention According to the present invention, N-(2,2-dialkoxyethyl)
From guanidine salt and S-methylisothiourea aqueous salt,
2-aminoimidazole can be produced in high yield.

In particular, if the product of the first step is not isolated and the second step is performed subsequently, the process operation becomes easier and a good yield can be obtained.

The method of the present invention, including the first and second steps and the isolation and purification operation, can be carried out only in an aqueous system, and therefore has the advantage that there is no danger in handling organic solvents.

Therefore, the present invention is extremely useful industrially.

Claims (1)

[Claims] 1. Aminoacetaldehyde dialkyl acetal and S
- A first step of reacting the aqueous salt of methylisothiourea in an aqueous medium to obtain an N-(2,2-dialkoxyethyl)guanidine salt, and the produced N-(2,2-dialkoxyethyl)guanidine. In carrying out the second step of manufacturing 2-aminoimidazole or its salt by cyclizing the salt in the presence of a strong acid, the cyclization reaction in the second step is performed using N-(2,2-dialkoxyethyl ) A method for producing 2-aminoimidazole or a salt thereof, which is carried out in the presence of 0.05 to 0.5 equivalents of a strong acid per mole of guanidine salt. 2. The production according to claim 1, wherein after the first step, the second step is carried out without isolating the generated N-(2,2-dialkoxyethyl)guanidine salt. Law. 3. The production method according to claim 2, wherein the isolation of the N-(2,2-dialkoxyethyl)guanidine salt after the completion of the second step is carried out only in an aqueous system.