JPH0249773A - Production of 4-methyl-5-((2-aminoethyl)-thiomethyl)-imidazole - Google Patents

Abstract

PURPOSE:To quantitatively produce the subject compound in high quality by reacting 4-methylimidazole with thiazolidine, discharging and separating the reaction liquid from the reaction system while keeping the concentration of the obtained product at a specific mol% and recycling the remaining part to the reaction system. CONSTITUTION:The objective compound useful as a synthetic intermediate for cimetidine which is a histamine H2 receptor antagonistic agent can be produced by reacting 4-methylimidazole with thiazolidine in a mineral acid, discharging the reaction liquid from the reaction system while keeping the molar concentration of the obtained 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole to <=70mol% based on the sum of 4-methylimidazole and 4-methyl-5-[(2-aminoethyl)- thiomethyl]-imidazole and separating the liquid containing 4-methyl-5-[(2- aminoethyl)-thiomethyl]imidazole by electrodialysis, etc. The remaining part is used by recycling to the reaction system.

Description

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

4-Methyl-5-[<2-aminoethyl)-thiomethyl]-imitazole 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) As a conventional method for obtaining 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole, for example, Japanese Patent Application Laid-Open No. 132568/1983 describes
After reacting 4-methylimidazole and thiazolidine at a reaction temperature of 0°C and a reaction time of 10 hours, hydrochloric acid was distilled off under reduced pressure, and 4-methyl-5 -[(2-aminoethyl)
-Thiomethyl 1-imidazole was obtained in a yield of 68%.

(Problems to be Solved by the Invention) In the conventional method of reacting 4-methylimidazole and thiazolidine in excess concentrated hydrochloric acid, a sequential reaction of the target product 4-methyl-5-hydroxylmethyl-imidazole proceeds, In addition, the reaction solution containing the product 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole contains unreacted raw materials such as 4-methylimidazole, thiazolidine, and hydrochloric acid. In addition, since it contains by-products from reactions that are considered to be sequential reactions, purification efficiency is low when trying to separate high-quality products, and it is virtually impossible to reuse unreacted raw materials. There is.

The present inventor conducted extensive research to improve the drawbacks of conventional methods, and as a result of detailed analysis of the reaction of 4-methylimidazole and thiazolidine in mineral acids, it was found that the 4-
Methyl-5-[(2-aminoethyl)-thiomethyl1-
Until the molar concentration of imidazole reaches 70 mol% based on the combined mole number of 11-methylimidazole and 11-methyl-5[(2-aminoethyl)-thiomethyl]-imidazole, that is, the conversion rate of 4-methylimidazole. is 7
4-methyl 5-[(2
The selectivity of -aminoethyl)-thiomethylcoimidazole is almost constant, but when the conversion rate is increased, the product 4-methyl-5[(2-aminoethyl)-thiomethyl]
- A reaction considered to be a sequential reaction of imidazole proceeds,
It was found that the selectivity decreased.

(Another Means to Solve the Problems) The present invention provides a method for producing 4-methyl-5[(2-aminoethyl)-thiomethyl]-imidazole by reacting 4-methylimidazole and thiazolidine in a reaction system in a mineral acid. , the molar concentration of 4-methyl-5-[(2-aminoethyl)-thiomethylcoimidazole in the reaction system is 4-methylimidazole and 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole. For the total number of moles,
While maintaining the concentration of 4-methyl-5[(2-aminoethyl) to 70 mol% or less, remove the reaction solution from the reaction system.
- A method for producing 4-methyl-5[(2-aminoethyl)-thiomethyl]-imidazole, characterized in that one portion containing thiomethylcoimidazole is separated and the remainder is recycled to the reaction system for use. be.

In the present invention, -1-methyl-5''(2
-aminoethyl)-thiomethyl]-imidazole has a molar concentration of 4-methylimidazole and 4methyl-5-[(2
-aminoethyl)-thiomethyl]-imitazole, 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, the reaction system can be maintained under these conditions by controlling the reaction temperature in the reactor and the residence time of the reaction solution.9 In the case of a bunch reaction, this also means the end of the reaction.

The tl-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, PL acid, phosphoric acid, etc.

The thiazolidines used in the method of the invention are used as free bases or as mineral acid salts.

As the mineral acid used in the method of the present invention, hydrohalic acid such as hydrochloric acid and hydrobromic acid, F, acid, phosphoric acid, etc. can be used.

Moreover, the molar ratio of 4-methylimidazole and thiazolidine as raw materials is 0.9 to 1.1, preferably equimolar.

The amount of mineral acid to be used is preferably 2 to 8 times the mole of 4-methylimidazole 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 mole.

A preferred method for carrying out the reaction of the 4-methylimidazole of the present invention and thiazolidine in a reaction system in a mineral acid is as follows:
4-Methylimidazole hydrochloride aqueous solution and thiazolidine hydrochloride aqueous solution are continuously fed into mineral acid,
The reaction is preferably carried out at a temperature of 120 to 150°C. 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.

In the present invention, the product 4-methyl-54(2-aminoethyl)thiomethyl]-
Methods for separating imitazole and unreacted raw materials include column separation and electrodialysis, with electrodialysis being particularly preferred.

The electrodialysis device used in the present invention is a conventional electrodialysis device in which a large number of cation exchange membranes and anion exchange membranes are arranged alternately, and a pair of electrodes are 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, causing cation exchange! ! !
! It passes through the membrane, moves to the next room, and is blocked by an anion exchange membrane. At this time, by using a suitable exchange membrane such as AC-110 (manufactured by Asahi Kasei Corporation), raw materials with a smaller molecular weight than the product pass through the cation exchange membrane, and the product with a larger molecular weight, 11-methyl-5 -[(2-Aminoethyl)-thiomethyl 1-imidazole permeation is blocked and separation takes place.

The internal solution containing the product 11-methyl-5-[(2-aminoethyl)diomethyl]-imitazole is used as is in the next step. Further, if necessary, it can be obtained as a crystal by concentrating the internal compound and then crystallizing it in a poor solvent such as 1-propanol.

The external solution containing the original v1 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, 71-methyl-5[(2-
When the molar concentration of 1-imidazole (aminoethyl)-thiomethyl is 4-methylimidazole and 4-methyl-
70 mol% or less, preferably 60 to 1, based on the total number of moles of aminoethyl)-thiomethyl]-imidazole
Extracting the reaction solution out of the reaction system while maintaining the concentration at 0 mol% substantially prevents the generation of byproducts due to sequential reactions.
Aminoedyl)-diomethyl]-imidazole is obtained in high quality. In addition, by separating the unreacted raw material f1 from the anti-1,6 liquid and recycling the reaction system to the reaction system, the anti-1,
It is useful in that it can almost quantitatively convert 6 raw materials 1 into reaction products.

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

Example-1 4-methylimidazole 16 to 811 g of 36 wt% hydrochloric acid
4 g and 250 g of thiazolidine hydrochloride were dissolved. This mixture was heated and stirred in an autoclave at 140°C for 3 hours. 1225 g of the resulting reaction solution contained 244 g of 4-methyl-5-C(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride, 118 g of 4-methylimidazole hydrochloride, other raw materials, and hydrochloric acid, and 4- The conversion rate of methylimidazole was 50°6.

Next, this reaction solution was used as the internal liquid, 1000 g of water was used as the external liquid, and
Electric Pi! Dissolved in sodium sulfate at 5° as a solution;
It was applied to an electrodialysis machine using a commercially available commercially available product. During the electrodialysis, the external solution was replaced with 1000 g of water and further electrodialysis was carried out.

Finally, 172 g of 4-methyl-5-C<2aminoethyl)-thiomethylcoimitazole dihydrochloride was used as the internal solution.
and 410 g of water, and 1-methyl')-[(2-aminoethyl) as an external liquid.
-thiomethyl]-imitazole dihydrochloride 72g1.1
-Methylimidazole hydrochloride 118 g of a candy raw material and 2,634 g of a liquid containing hydrochloric acid were 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. 162 g of dihydrochloride were obtained.

Example-2 The external liquid obtained in Example-1 was reduced to 1010 g under reduced pressure;
It was deflated. This: f! Add 57 g of 4-methylimidazole, 87 g of thiazolidine hydrochloride and 71 g of 36 g L% hydrochloric acid to the 4-condensed liquid and place in an autoclave at 1-10°C, 2
Allowed time to react. -1-methyl-
It contained 243 g of 5-[(2-aminoethyl)-thiomethylcoimidazole dihydrochloride, 119 g of 4-methylimidazole hydrochloride, 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]-imidazole dihydrochloride 1
An internal liquid consisting of 70 g and 405 g of water was obtained.

The external liquid was concentrated under reduced pressure and then recycled to the next reaction.

Example-3 In Figure-1, 6.75g/rnin from conduit 1
8% by weight hydrochloric acid, 4- at 5.75 g/min from conduit 2.
Methylimidazole and thiazolidine hydrochloride were each supplied to the mixing tank 4 from the conduit 3 at a rate of 88 g/min. 1.10 at 21.3g/min through conduit 5 from mixing tank 4
It was maintained at °C and fed to the tfS reactor 6.

The residence time in reactor 6 was 2.5 hours.

It was extracted from the reactor 6 through the conduit 7 at a rate of 162 g/min. This anti-tJ solution contains ・1-methyl-5=[(2-
Aminoethyl)-thiomethyl]-imidazole dihydrochloride 15.1% by weight, 4-methylimidazole hydrochloride 7
．． Containing 3% by weight of candy raw material and hydrochloric acid, the conversion rate of 4-methylimidazole was equivalent to 50%. This reaction solution was cooled to below 50°C in a cooler 8, and passed through a conduit 9 to a
Ion exchange using 5% sodium sulfate aqueous solution as the liquid
The membrane [AC-110 (manufactured by Asahi Kasei Corporation)] was supplied as the internal liquid of the electrodialyzer 10.Water 2 was supplied through the conduit 11.
72 g/min was supplied as external fluid to the electrodialyzer 10. A liquid having a concentration of 17.44% by weight of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole dihydrochloride was obtained from conduit 12 at a rate of 98 g/min.

1,582 g of this 't was concentrated and poured into 1,000 g of 1-propyl alcohol, and the precipitate was filtered and dried under reduced pressure to give white crystals of 4-methyl-5-[(2-aminoethyl)-thiomethyl]- 162 g of imitazole dihydrochloride was obtained.

The external liquid obtained from the electrodialyzer 10 is transferred from the conduit 13 to 336
．． It is extracted at a rate of 3 g/min, supplied to the concentrator 14, and concentrated to give 4-methylimidazole hydrochloride 8.4% by weight, 4
-Methyl-5-[(2-aminoethyl)-thiomethyl]
- Imidazole dihydrochloride Adjust to a liquid containing 5.2% by weight of candy raw material and hydrochloric acid, and pass through conduit 15 at 141g/'
It was returned to the reactor 5 at h.

(Effect of the invention) When producing 4-methyl-5-[(2-aminoethyl)-1,000-methyl]-imidazole by reacting the 4-methylimidazole and thiazolidine of the present invention in a reaction system in a mineral acid, the reaction system The molar concentration of 4-methyl 5-[(2-aminoethyl)-thiomethyl]imidazole is the combined molar concentration of 4-methylimidazole and 4-methyl-5-C(2-aminoethyl)thiomethylcoimidazole For the number,
Extracting the reaction solution from the reaction system while keeping the concentration below 70 mol % is to substantially prevent the generation of byproducts due to sequential reactions, and the reaction products 4-methylimidazole and 4-methyl-5-[ (2-Aminoethyl)-thiomethyl]-imidazole can be easily obtained in high quality. Further, 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. The present invention provides a method for continuously performing a process including reaction, separation, and recovery and reuse of unreacted raw materials, and is an industrially advantageous method.

[Brief explanation of the drawing]

1 is a process diagram showing one embodiment of the present invention. mixing tank reactor Cooler electrodialysis machine C agricultural compressor

Claims (2)

[Claims] (1) When 4-methylimidazole and thiazolidine are reacted in a reaction system in mineral acid to produce 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole, 4-methyl The molar concentration of -5-[(2-aminoethyl)-thiomethyl]-imidazole is relative to the total number of moles of 4-methylimidazole and 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole, The reaction solution is drawn out of the reaction system while keeping the concentration below 70 mol%, and the solution containing 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole is separated from the reaction solution, and the remainder is recycled to the reaction system. 4 characterized by being used in circulation
-Methyl-5-[(2-aminoethyl)-thiomethyl]
-Production method of 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.