JPS6360971A - Production of imidazole derivative - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides N-cyano-N'- represented by formula (n), which is useful as an antihistamine agent that acts on histamine receptors other than H-1 receptors. This invention relates to a novel method for producing methyl-N'-(2-((4-methyl-5-imidazolyl)methylthio]ethyl)guanidine (-ship name: cimetisine) or cimetidine-related compounds.

[Conventional technology]

Existing methods for synthesizing the compound represented by formula (II) below include:
Broadly speaking, there are two types of methods.

The first method is to synthesize from imidazole derivatives,
For example, Japanese Patent Publication No. 49-75574, Japanese Patent Publication No. 51-1
It is shown in the No. 25074 publication. The second method is to synthesize the compound represented by formula (II) by synthesizing an imidazole ring in the last step of a series of synthetic reactions. For example, cimetidine is synthesized from α-diketone jA 6-form. It is disclosed in Spanish Patent No. 455991 (Chemical Abstracts Vol. 89, 146904 g). The first method uses an expensive imidazole derivative as a starting material and involves a multi-step reaction, so it has the drawback of high raw material costs.

Furthermore, the second method had the disadvantage of using diacetyl, which is expensive and has a bad odor, as a starting material. The present invention provides a new method for producing imidazole derivatives that solves the above-mentioned drawbacks of conventional methods.

The synthetic intermediate shown in formula (1) is disclosed in the applicant's patent application “Cyanoguanidine derivatives and their production method” dated the same date as the present application.
As shown in , it can be easily obtained in high yield using an inexpensive raw material called methyl vinyl ketone. A feature of the present invention is that by forming an imidazole ring in the synthetic intermediate (formula [I]), the imidazole derivative represented by formula Cn) can be economically advantageously obtained. In addition, among the compounds shown with 2 [■],
The above-mentioned compound in which R is a methyl group is an important compound as a gastric ulcer treatment drug (-ship name: Cimethicin).

[Problem that the invention seeks to solve]

The present invention relates to a completely new method for synthesizing the compound represented by ni(n).

The haloketone derivative represented by the formula [■] can be easily produced using inexpensive raw materials, for example, as shown in the patent application "Cyanoguanidine derivatives and their production method" filed on the same date as the present application by the applicant. be able to.

A compound represented by formula (II) can be synthesized by converting a haloketone derivative represented by formula (1) into an imidazole derivative. Generally, there are two methods for synthesizing imidazole derivatives from α-herocarbonyl compounds. Namely, Hemitssie Herichte (Che
Mische Berichte) Volume 34, page 637 (
The method of reacting an α-halocarbonyl compound with amidine g3 body as shown in 1901) and Angewandte Chemie 2.
This is a method of reacting an α-halocarbonyl compound with an amide derivative, as shown in Vol. 3, p. 753 (1959). In order to synthesize the compound represented by formula (II) from the compound represented by formula [■], the above two methods were tried, but the compound represented by formula CII) could not be obtained at all. Therefore, the present invention was completed by intensively studying a completely new method for synthesizing the compound of formula (II) from the compound of formula (1).

[Summary of the invention]

The present invention is based on the general formula (1) [wherein, X is a chlorine atom or a bromine atom, and R is hydrogen or a lower alkyl group]. ] A haloketone derivative represented by the formula CII) is reacted with formamidine in the presence of ammonia to form the formula CII) 7, CN [wherein R is the same as above. The present invention relates to a method for producing an imidazole derivative, which is characterized by obtaining an imidazole derivative represented by the following.

In the haloketone derivative represented by formula (1) according to the present invention, the lower alkyl group used for R is a methyl group,
Examples include ethyl group, n-propyl group, isopropyl group, n-butyl group, and 5ec-7''thyl group.

The haloketone derivative represented by (1) can be easily produced using inexpensive raw materials, for example, according to the method described in the application "Cyanoguanidine derivatives and their production method" filed by the present applicant on the same date as the present application.

The amount of ammonia used is 2 to 10100 Or! per 1 mon of the compound represented by 2N! , more preferably 5 to 100 moE. The formamidine used can be used in the form of a salt with acetic acid, hydrochloric acid, etc.
The amount used is 1 to 50 m, more preferably 2 to 10 m, per moj2 of the compound represented by formula (I).
It is o l. The reaction temperature is -50 to 150°C, more preferably 0 to 100°C. The reaction time varies depending on the reaction temperature, but is preferably 5 minutes to 48 hours, more preferably 3 hours.
The time is from 0 minutes to 6 hours. Although this reaction can be carried out without using a solvent, it is preferable to use a solvent. Solvents include water, methanol, ethanol, propatool, ethylene glycol, glycerin, benzene, toluene,
Examples include acetonitrile, dichloromethane, ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and more preferably alcohols such as ethylene glycol and methanol.

The amount of solvent used is 1 to 1001, more preferably 1 to 201, per moff of the compound of formula (I).

After completion of the reaction, in order to separate and purify the generated compound represented by formula (II) from the reaction mixture, a known method such as solvent extraction, washing, solvent distillation, recrystallization, column chromatography, etc. can be appropriately selected. , can be easily implemented by using in combination.

Hereinafter, the method of the present invention will be specifically explained using examples.

Example I N-(2-chloro-3-oxobutylthio)ethyl-N
'-Cyano-N''-methylguanidine 0.13 g (
0.5 mmol) to 0.40 g of formamidine hydrochloride (
5.0 mmol) and then 0.85 g of ammonia.
5 g of ethylene glycol containing (50,0 mmol)
and stirred at room temperature for 3 hours. After the ammonia in the reaction mixture was distilled off under reduced pressure, the residue was subjected to high performance liquid chromatography (column Solhac ODS, developing solvent methanol: water: nitriethylamine acetate = 375:
857: 1:1, Flow'FJ 1. Omf/min
), the target N-cyano-N'-
It was found that methyl-N''-(2-((5-methyl-E-imidazol-4-yl)methylthio)ethyl]guanidine (cimetidine) was produced in a yield of 17%.

Examples 2 to 3 The reaction was carried out in the same manner as in Example 1, except that the ammonia-containing solvent listed in Table 1 was used instead of the ammonia-containing ethylene glycol in Example 1, and cimetidine was produced as shown in Table 1. was produced in a yield of .

Table 1 □-1* Determination by HPLC Example 4 In Example 3, methanol was added to the solvent water for 1 m
The reaction was carried out in the same manner as in Example 3, except that 1 was added. Analysis of the reaction solution by high performance liquid chromatography revealed that cimetidine was produced at a yield of 8%. The reaction mixture was extracted with ethyl acetate, and ethyl acetate was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography (elution medium: dichloromethane:methanol-10:1) to obtain the desired cimetidine 6.

(Yield 5%) Example 5 N-(2-chloro-3-oxobutylthio)ethyl-N
r-cyano-N"-methylguanidine 0.13g (0
, 5 mmol) to 0.40 g of formamidine hydrochloride (5
, 0 mmol) and 5.00 g (294 mmol) of ammonia were added, followed by stirring in an autoclave for 3 hours. After distilling off the ammonia in the reaction mixture, the residue was analyzed by high performance liquid chromatography, and it was found that cimetidine was produced at a yield of 5%.

Example 6.7 In Example 1, instead of performing the reaction temperature at room temperature, Table 2
When the reaction was carried out at the stated temperature, cimetidine was produced in the yield shown in Table 2.

Table 2 *) Determination by IPLc Example 8 N-(2-bromo-3-oxobutylthio)ethyl-N
r-cyano-N"-methylguanidine 0.15g (0,
0.52 g (5,0 mmol) of formamidine acetate (5 mmol)
5.00 g (294 mmol) of ammonia were added thereto, and the mixture was stirred in an autoclave at room temperature for 3 hours.

After distilling off the ammonia in the reaction mixture, the residue was analyzed by high performance liquid chromatography, and it was found that the target N
-Cyano-N'-methyl-N''-C2-((5-methyl-IH-imidazol-4-yl)methylthio)ethyl]guanidine (cymetidine) was found to be produced in a yield of 13%. .

Claims (1)

[Claims] (1) General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, X is a chlorine atom or a bromine atom, and R is a hydrogen atom or a lower alkyl group) Haloketones General formula [II] characterized by reacting a derivative and formamidine in the presence of ammonia ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] Imidazole derivatives represented by (in the formula, R is the same as above) manufacturing method.