JPH0586945B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention provides N-cyano-N'-methyl-N''- represented by the formula [], which is useful as an antihistamine agent that acts on histamine receptors other than H-1 receptors.
{2-[(4-methyl-5-imidazoyl)methylthio]ethyl}guanidine (generic name cimetidine)
Alternatively, the present invention relates to a novel method for producing cimetidine-related compounds. [Prior Art] Existing methods for synthesizing the compound represented by the following formula [] can be broadly classified into two types. The first method is to synthesize from imidazole derivatives, for example, Japanese Patent Application Laid-Open No. 49-75574, Japanese Patent Publication No. 51-125074
It is shown in the publication No. The second method is to synthesize the compound represented by the formula [ ] by synthesizing the imidazole ring in the final step of a series of synthetic reactions.For example, the method of synthesizing cimetidine from an α-diketone derivative is It is shown in Patent No. 455991 (Chemical Abstracts Vol. 89, 146904g). 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 [] has the general formula

[In the formula, X is a chlorine atom or a bromine atom. ]

The methyl vinyl ketone derivative represented by general formula

[In the formula, R is a hydrogen atom or a lower alkyl group. ]

The mercaptoguanidine derivative represented by
It is synthesized by reacting with The method for producing this synthetic intermediate is described in the patent application ``Cyanoguanidine Derivatives and Method for Producing the Same'' [Japanese Patent Application No. 61-203640 (Japanese Unexamined Patent Publication No. 63-60963)]. A feature of the present invention is that the imidazole derivative represented by the formula [] can be economically advantageously obtained by forming an imidazole ring in the synthetic intermediate (formula []). Among the compounds represented by the formula [], those in which R is a methyl group are important compounds as gastric ulcer therapeutics (generic name: cimetidine). [Problems to be Solved by the Invention] The present invention relates to a completely novel method for synthesizing a compound represented by the formula []. The haloketone derivative represented by the formula [] can be easily produced using inexpensive raw materials, for example, as shown in the above-mentioned "Cyanoguanidine derivative and method for producing the same". By converting the haloketone derivative represented by the formula [] into an imidazole derivative, the formula []
The compound shown can be synthesized. Generally, there are two methods for synthesizing imidazole derivatives from α-halocarbonyl compounds. That is, Chemische Berichte (Chemische Berichte)
Berichte, Vol. 34, p. 637 (1901), a method for reacting α-halocarbonyl compounds with amidine derivatives, and Angewandte Chemie, Vol. 23, p. 753 (1959), This is a method of reacting a halocarbonyl compound with an amide derivative. In order to synthesize the compound represented by the formula [] from the compound represented by the formula [], the above two methods were tried, but the compound represented by the formula [] could not be obtained at all. Therefore, the present invention was completed by intensively investigating a novel method for synthesizing a compound of formula [] from a compound of formula []. [Summary of the invention] The present invention relates to the general formula []

[In the formula, 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 [] is reacted with formamidine in the presence of ammonia.

embedded image [In the formula, 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 [] according to the present invention, examples of the lower alkyl group used for R include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, and sec-butyl group. be able to. The haloketone derivative represented by the formula [] 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 1000 mol, more preferably 5 to 100 mol, per 1 mol of the compound represented by formula []. The formamidine used can be used in the form of a salt with acetic acid, hydrochloric acid, etc., and the amount used is 1 to 50 mol, more preferably 2 to 10 mol, per 1 mol of the compound represented by the formula []. Reaction temperature is -50~150℃,
More preferably, the temperature is 0°C to 100°C. The reaction time varies depending on the reaction temperature, but is 5 minutes to 48 hours, more preferably 30 minutes to 6 hours. Although this reaction can be carried out without using a solvent, it is preferable to use a solvent. Examples of the solvent include water, methanol, ethanol, propanol, ethylene glycol, glycerin, benzene, toluene, acetonitrile, dichloromethane, ether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, and more preferably ethylene glycol and methanol. Alcohols such as The amount of solvent used is 1 to 100, more preferably 1 to 20, per 1 mol of the compound of formula []. After completion of the reaction, to separate and purify the generated compound represented by the formula [] from the reaction mixture, appropriately select a known method such as solvent extraction, washing, solvent distillation, recrystallization, column chromatography, etc. , can be easily implemented by using in combination. Hereinafter, the method of the present invention will be specifically explained with reference to Examples. Example 1 N-{2-(2-chloro-3-oxobutylthio)ethyl}-N′-cyano-N″methylguanidine
0.40 g of formamidine hydrochloride in 0.13 g (0.5 mmol)
(5.0 mmol) and then 0.85 g of ammonia
5g of ethylene glycol containing (50.0 mmol)
and stirred at room temperature for 3 hours. After distilling off the ammonia in the reaction mixture under reduced pressure, the residue was subjected to high performance liquid chromatography (column solvac).
ODS, developing solvent methanol:water:acetic acid:triethylamine=375:857:1:1, flow rate 1.0ml/
The target N-cyano-N′-methyl-N″-[2-{(5-methyl-1H-
imidazol-4-yl)methylthio}ethyl]
It was found that guanidine (cimetidine) was produced at a yield of 17%. Examples 2 to 3 A 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 listed in Table 1. was produced in a yield of .

[Table] Example 4 A reaction was carried out in the same manner as in Example 3 except that 1 ml of methanol was further added to the water used as the solvent. When the reaction solution was analyzed by high performance liquid chromatography, it was found 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 subjected to silica gel column chromatography (elution solvent dichloromethane:methanol = 10:1)
6 mg of the desired cimetidine was obtained.
(Yield 5%) Example 5 0.13 g (0.5 mmol) of N-{2-(2-chloro-3-oxobutylthio)ethyl}-N'-cyano-N''-methylguanidine was dissolved in formamidine hydrochloride.
0.40 g (5.0 mmol) and 5.00 g (294 mmol) of ammonia were added, 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 cimetidine was produced at a yield of 5%. Examples 6 and 7 In Example 1, the reaction was carried out at the temperature shown in Table 2 instead of at room temperature, and cimetidine was produced at the yield shown in Table 2.

[Table] Example 8 0.15 g (0.5 mmol) of N-{2-(2-bromo-3-oxobutylthio)ethyl}-N'-cyano-N''-methylguanidine and formamidine acetate
0.52 g (5.0 mmol) and 5.00 g (294 mmol) of ammonia were added, 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 the target N-cyano-N'-methyl-N''-[2-{(5-methyl 1H-imidazole-
It was found that 4-yl)methylthio}ethyl]guanidine (cymetidine) was produced in a yield of 13%.

Claims (1)

[Claims] 1 General formula () [In the formula, X is a chlorine atom or a bromine atom, and R is a hydrogen atom or a lower alkyl group] A haloketone derivative represented by the formula (2) and formamidine are combined in ammonia. A method for producing an imidazole derivative represented by the general formula [] [Chemical formula] [In the formula, R is the same as above], characterized in that the reaction is carried out in the coexistence of the following compounds: