JPH0276859A - Production of 4-methyl-5-((2-aminoethyl)-thiomethyl)-imidazole - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an intermediate for cimetidine without producing by-product while quantitatively converting unreacted material by reacting 4-methylimidazole with an addition product of cysteamine and formaldehyde in a mineral acid at specific molar concentrations. CONSTITUTION:Reaction liquid produced by reacting 4-methylimidazole with an adduct of cysteamine and formaldehyde in a mineral acid is extracted from the reaction system while keeping the molar concentration of 4-methyl-5-[(2- aminoethyl)-thiomethyl]-imidazole in the reaction system to <=70mol% based on the sum of 4-methylimidazole and 4-methyl-5-[(2-aminoethyl)- thiomethyl]imidazole. The liquid containing 4-methyl-5-[(2-aminoethyl)- thiomethyl]-imidazole is separated from the reaction liquid. The residue is reused by recycling to the reaction system.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel process for producing 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole.

4-Methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole obtained in the present invention is histamine H2-
This compound has important uses as a synthetic intermediate for cimetidine, which is known as a receptor antagonist.

(Prior art) Conventional methods for obtaining 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imitazole include: ■ Reacting 4-methyl-5-hydroxylmethyl-imidazole with cysteamine in concentrated hydrochloric acid. (Japanese Unexamined Patent Publication No. 119867), and (1) A method of reacting 4-methylimidazole in concentrated hydrochloric acid with cysteamine and formaldehyde or thiazolidine (Unexamined Japanese Patent Application No. 1983-119867).
No. 132568), etc. are known.

(Problems to be Solved by the Invention) The disadvantage of the method of reacting 4-methyl-5-hydroxylmethyl-imidazole with cysteamine in concentrated hydrochloric acid as disclosed in JP-A-53-119867 is that 4-methyl-5-hydroxylmethyl-imidazole It is to start from. This is because 4-methyl-5-hydroxylmethyl-imitazole is produced by a method of reacting 4-methylimidazole with formaldehyde in hydrochloric acid, or by a method of reacting 4-methylimidazole with formaldehyde in hydrochloric acid.
Although it can be obtained by reduction of 5-carboxylic acid ester, it has the disadvantage that it requires complicated means and the yield is low.

The conventional method of reacting 4-methylimidazole in concentrated hydrochloric acid with cysteamine and formaldehyde or thiazolidine as disclosed in JP-A No. 54-132,568 is different from the method of reacting 4-methyl-5-droxylmethyl- as disclosed in JP-A-53-119,867. As an improved method of reacting imidazole with cysteamine in concentrated hydrochloric acid, a method for obtaining 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole in one step from 4-methylimidazole is disclosed.

The present inventor analyzed in detail the batch reaction of 4-methylimidazole, cysteamine, and formaldehyde, and found that 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole was selected for the conversion rate of 4-methylimidazole. The relationship between the rates is shown in Figure 1, and since the reactions occur sequentially from the beginning of the reaction, a decrease in selectivity was observed.

For this reason, when trying to isolate a product from a reaction solution, it is essential to remove byproducts as well as unreacted raw materials, which results in low production efficiency and virtually impossible reuse of unreacted raw materials. Defects were recognized.

The present inventor conducted intensive research to improve the drawbacks of conventional methods, and as a result, compared to the conventional method of simultaneous reaction of 4-methylimidazole, cysteamine, and formaldehyde,
As a result of detailed analysis of the reaction between an adduct obtained by pre-mixing cysteamine and formaldehyde and 4-methylimidazole in mineral/acid, that is, a two-step reaction, we found that 4-methyl-5- The molar concentration of [(2-aminoethyl)-thiomethyl]-imidazole is 70 mol% with respect to the total number of moles of 4-methylimidazole and 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole. until the conversion of 4-methylimidazole reaches 70 mol%.
-Methyl-5-[(2-aminoethyl)-thiomethyl]
- It has been found that the selectivity of imidazole is almost quantitative.

(Means for Solving the Problems) The present invention involves reacting an adduct of cysteamine and formaldehyde with 4-methylimidazole in a mineral acid to produce 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole. During production, 4-methyl-5-
The molar concentrations of [(2-aminoethyl)-thiomethyl]-imidazole are 4-methylimidazole and 4-methyl-5
-[(2-Aminoethyl)-thiomethyl]-Imidazole, the reaction solution is extracted out of the reaction system while keeping the total number of moles at 70 mol% or less, and 4-methyl-
5" [(2-aminoethyl)-thiomethyl]-imidazole-containing liquid is separated and the remainder is recycled to the reaction system for use. The present invention relates to a method for producing [thiomethyl]-imidazole.

In the present invention, 4-methyl-5-[(2-
The molar concentrations of 4-methylimidazole and 4-methyl-5-[(2
-aminoethyl)-thiomethyl]-imidazole, 70 mol% or less, preferably 60 to 4
The purpose of maintaining the content at 0 mol % is to substantially prevent the production of by-products due to sequential reactions, and has a special meaning in terms of the process. In addition, in order to maintain the reaction system under these conditions, in a continuous reaction, the reaction temperature and residence time of the reaction solution in the reactor can be controlled. In the case of a batch reaction, it also means the end of the reaction.

The 4-methylimidazole used in the method of the present invention is used in the form of a free base or a salt neutralized with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.

The adduct of cysteamine and formaldehyde used in the method of the present invention can be easily obtained by mixing equimolar amounts of cysteamine and formaldehyde at room temperature.

The cysteamine used in the method of the invention is used as a free base or as a mineral acid salt.

The formaldehyde used in the method of the present invention is used as water 78M containing 30 to 40% by weight of formaldehyde or as formaldehyde.

The mineral acids used in the method of the present invention include hydrohalic acids such as hydrochloric acid and hydrobromic acid, sulfuric acid, and phosphoric acid.

The mineral acid is preferably used in an amount of 2 to 8 times the amount of 4-methylimidazole used as a raw material, and from the viewpoint of economy and productivity, it is preferably used in an amount of 2 to 5 times the amount of 4-methylimidazole.

Further, the molar ratio of the raw material adduct of cysteamine and formaldehyde to 4-methylimidazole is 0.9 to 1.1, preferably equimolar.

A preferred method for reacting the adduct of cysteamine and formaldehyde of the present invention with 4-methylimidazole in a mineral acid is to continuously prepare an aqueous solution of the adduct of cysteamine and formaldehyde and an aqueous solution of 4-methylimidazole hydrochloride in a mineral acid. The reaction should be carried out at a temperature of 100 to 180°C, preferably 120 to 150°C.6 The residence time of the reaction solution varies depending on the amount and concentration of the mineral acid and the reaction temperature, but is usually 30 minutes to 10 hours. It is.

In the present invention, methods for separating the product 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole and unreacted raw materials from the reaction solution extracted from the reaction system include column separation method and electric There are dialysis methods, but electrodialysis is preferred.

Electrodialysis device used in the present invention! This is commonly used and consists of a large number of cation exchange membranes and anion exchange membranes arranged alternately, and a pair of electrodes arranged at both ends. In a chamber with an anion exchange membrane on the anode side and a cation exchange membrane on the cathode side, ionized cations move toward the cathode, pass through the cation exchange membrane, and move to the next chamber, where their permeation is blocked by the anion exchange membrane. Ru. At this time, a suitable exchange membrane such as AC-110 (Asahi Kasei) is used.
Co., Ltd.), raw materials with a lower molecular weight than the product pass through the cation exchange membrane, and the product with a larger molecular weight, 4-methyl-5-[(2-aminoethyl)-
thiomethyl]-imidazole is blocked from permeation and separated.

The internal solution containing the product 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole is used as is in the next step. If necessary, crystals can be obtained by concentrating the internal solution and crystallizing it in a poor solvent such as 1-10 panol.

The external liquid containing the raw material can be recycled to the reaction system as it is or after being concentrated or diluted to an appropriate concentration.

(Function) In the present invention, 4-methyl-5-[(2-
The molar concentrations of 4-methylimidazole and 4-methyl-5-[(2
-aminoethyl)-thiomethyl]-imidazole, 70 mol% or less, preferably 60 to 4
The purpose of extracting the reaction solution out of the reaction system while maintaining it at 0 mol% is to substantially prevent the generation of byproducts due to sequential reactions, and the reaction product 4-methyl-5-[(2-aminoethyl) -Thiomethyl]-imidazole can be obtained in high quality. Furthermore, by separating unreacted raw materials from the reaction solution and recycling them to the reaction system, the unreacted raw materials can be almost quantitatively converted into reaction products.

(Examples) Next, the present invention will be specifically explained using Examples, but these are merely illustrative and the present invention is not limited to these Examples.

(Reference example) "Synthesis of a one-dimensional compound of cysteamine and formaldehyde" Add 302 g of a 75% by weight aqueous solution of cysteamine hydrochloride to 37% by weight formaldehyde.
Is the adduct of cysteamine and formaldehyde dissolved in water by adding it below 0°C? ? 464 g of N was obtained.

Example-1 4-methylimidazole 16 to 811 g of 36 wt% hydrochloric acid
4g and 464g of the aqueous solution of the cysteamine-formaldehyde adduct obtained in Reference Example were dissolved. The mixture was heated and stirred in an autoclave at 140°C for 2 hours. 4-methyl-5 was contained in 1439 g of the obtained reaction solution.
- Contained 244 g of [(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride, 118 g of 4-methylimidazole hydrochloride, other raw materials, and hydrochloric acid, and the conversion rate of 4-methylimidazole was 50%.

Next, this reaction solution was used as an internal solution, 1000 g of water was used as an external solution, and 5% sodium sulfate water was used as an electrode solution. During the electrodialysis, the external solution was replaced with 1000 g of water and further electrodialysis was carried out.

Finally, 794 g of a liquid consisting of 170 g of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride and 624 g of water was obtained as an internal liquid.
In addition, as an external liquid, 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imitazole dihydrochloride 74
2,640 g of a liquid containing 118 g of 4-methylimidazole hydrochloride, other raw materials, and hydrochloric acid was obtained.

The obtained internal solution was concentrated under reduced pressure and poured into 1-propyl alcohol, and the precipitated crystals were filtered and dried to give white crystals of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole. 159 g of hydrochloride was obtained.

Example-2 The external liquid obtained in Example-1 was concentrated to 1000 g under reduced pressure. 56 g of 4-methylimidazole,
Aqueous solution of cysteamine and pomaldehyde adduct 1
62 g and 70 g of 36% by weight hydrochloric acid were added and reacted in an autoclave at 140°C for 1 hour and 30 minutes. The resulting reaction solution contained 245 g of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride;
It contained 117 g of 4-methylimidazole hydrochloride, other raw materials, and hydrochloric acid, and had the same composition as the first reaction solution. By electrodialyzing this reaction solution in the same manner as in Example-1, 4
-Methyl-5-[(2-aminoethyl)-thiomethyl]
An internal solution consisting of 170 g of imidazole dihydrochloride and 620 g of water was obtained. The external solution was circulated to the concentrated sequential reaction under reduced pressure.

Example 3 In Figure 2, a 75% aqueous solution of cysteamine hydrochloride was supplied from conduit 1 at a rate of 90.8 g/h, and a 37% by weight formaldehyde aqueous solution was supplied from conduit 2 at a rate of 48,7 g/h, and It was supplied to reactor 5.

On the other hand, 4-methylimidazole hydrochloride aqueous solution was fed into reactor 5 at 49.2 g/h from conduit 6 at 106.8 g/h.
supplied to.

Reactor 5 was maintained at 140°C, and the residence time of the reaction liquid in reactor 5 was controlled to be 2 hours. The reaction solution was continuously extracted from the reactor 5 through the conduit 7 at a rate of 1397 g/h. Then, it was cooled down to 50°C or lower using a cooler 8. This solution contains the product 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride 17.
．． 46% by weight, 4-methylimidazole hydrochloride 8.4
This solution, which contains 8% by weight of other raw materials and hydrochloric acid and corresponds to a conversion rate of 50% of 4-methylimidazole, was passed through a conduit 9 to an ion exchange membrane [AC-110 ( [manufactured by Asahi Kasei Co., Ltd.] was supplied as an internal liquid of an electrodialysis device 10. Conduit 11
2,346 g/h of water was supplied as an external liquid to the electrodialyzer 10, and a 5% sodium sulfate and water gold solution was used as the electrolytic solution. A liquid having a concentration of 20.16% by weight of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imitazole dihydrochloride was obtained from conduit 12 at a rate of 726 g/h.

The external liquid obtained from the electrodialyzer 10 is transferred from the conduit 13 to 301
7 g/h, supplied to the concentrator 14 and concentrated,
In addition to 6.71% by weight of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride and 8.15% by weight of 4-methylimidazole hydrochloride, a liquid containing raw materials and hydrochloric acid was added. Adjust and pass through conduit 15 to 1454g
/h and returned to reactor 5.

After concentrating 100 g of the liquid obtained from conduit 12, it was poured into 150 g of -propyl alcohol, the precipitate was filtered, and when dried, white crystals of 4-methyl-5-[(2
19.2 g of -aminoethyl)-thiomethyl]-imidazole dihydrochloride was obtained.

(Effect of the invention) In producing 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole by reacting the adduct of cysteamine and formaldehyde of the present invention with 4'-methylimidazole in a mineral acid. , 4-methyl-5 in the reaction system
-[(2-Aminoethyl)-thiomethyl]-imidazole has a molar concentration of 4-methylimidazole and 4-methyl-
Extracting the reaction solution from the reaction system while keeping the amount of 5-[(2-aminoethyl)-thiomethyl]-imidazole at 70 mol% or less with respect to the total number of moles actually generates byproducts due to sequential reactions. The reaction product 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole can be easily obtained in high quality.
By separating the unreacted raw materials from the reaction solution and recycling them to the reaction system, the unreacted raw materials can be almost quantitatively converted into reaction products.The present invention enables the reaction, separation, and recovery and reuse of the unreacted raw materials. This is an industrially advantageous method because it provides a method for continuously carrying out processes including the following.

[Brief explanation of the drawing]

In Figure 1, the curve (1) is obtained by reacting the adduct of cysteamine and formaldehyde of the present invention with 4-methylimidazole in a mineral acid. Product 4 for the conversion rate of 4-methylimidazole in the raw material when producing
-Methyl-5-[(2-aminoethyl)-thiomethyl]
- Shows the change in selectivity of imidazole. Curve (2) shows the conversion rate of 4-methylimidazole and 4-methyl-5-[(2-aminoethyl )-Thiomethyl]-imidazole selectivity change. FIG. 2 is a process diagram showing one embodiment of the present invention. 3: Mixing tank 5: Reactor 8: Cooler 10: Electrodialyzer 14: ! A condenser patent applicant Nippon Shokubai Kagaku Kogyo Co., Ltd. Figure-1 Conversion rate (X)

Claims (2)

[Claims] (1) When reacting the adduct of cysteamine and formaldehyde with 4-methylimidazole in mineral acid to produce 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole, the reaction system 4-methyl-5-
The molar concentrations of [(2-aminoethyl)-thiomethyl]-imidazole are 4-methylimidazole and 4-methyl-5
-[(2-Aminoethyl)-thiomethyl]-Imidazole, the reaction solution is extracted out of the reaction system while keeping the total number of moles at 70 mol% or less, and 4-methyl-
4-Methyl-5-[(2-aminoethyl)-, which is characterized in that the liquid containing 5-[(2-aminoethyl)-thiomethyl]-imidazole is separated and the remainder is recycled to the reaction system for use. Process for producing [thiomethyl]-imidazole. (2) The method according to claim 1, wherein the method for separating the liquid containing 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole from the reaction liquid is electrodialysis.