JPH0567623B2 - - Google Patents

Description

[Detailed description of the invention]

This invention is based on the general formula

[Chemical formula] (In the formula, R ¹ and R ⁴ mean a lower alkyl group, and R ² and R ³ mean a lower alkylene group, respectively.)
This relates to a novel method for producing the imidazole derivative or its salt represented by the following formula.

[ka]

[In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as above, and X ¹ each represents a group represented by a halogen or cyanamide group] compound ()
This is done by applying In the starting compound (), the lower alkyl group represented by R ¹ includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary
Examples include linear or branched alkyl groups such as butyl, pentyl, and hexyl, and lower alkylene groups represented by R ² and R ³ include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene. , 2-methyltrimethylene, 2,2-dimethyltrimethylene, etc., and the lower alkylene groups of R ² and R ₃ may be the same or different. Good too. Examples of the lower alkyl group represented by R ⁴ in the other starting material compound ( ) include the same groups as the lower alkyl group of R ¹ above. Also,
Examples of the halogen represented by X ¹ include chlorine, bromine, and iodo. This reaction is usually carried out in a solvent, and examples of the vehicle include alcohols such as methanol, ethanol, propanol, butanol, and isopropyl alcohol, acetonitrile, methylene chloride, dimethylformamide, dimethyl sulfoxide, dioxane, and tetrahydrofuran. . The reaction temperature is usually cooled to room temperature. In addition, when using a compound in which X ¹ is halogen in the above general formula () as a raw material, triethylamine, pyridine, N-methylaniline, 1,5-diazabicyclo[5,4,
The reaction is preferably carried out in the presence of a base such as 0]-5-undecene. The imidazole derivative () produced by this method is isolated from the reaction mixture by a conventional method,
It can be purified and the free compound () may be converted into a desired salt such as a hydrochloride salt by conventional methods. Note that all the raw material compounds used in the method of the present invention can be produced by the methods described in Examples or by methods similar thereto. Next, the method of the present invention will be explained using examples. Example 1 (1) Cyanamide (18.5g) and N-cyano-S
-Methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]isothiourea (10.76 g) was added to an ethanol solution (120 ml) of sodium metal (1.01 g), and the resulting mixture was stirred for 1.5 hours. Heat to reflux. The reaction solution was concentrated under reduced pressure, the residue was added to cold water (50 ml), the pH was adjusted to 4.5 with 10% hydrochloric acid, and the mixture was cooled in an ice bath for 1 hour. The precipitate was collected by filtration, washed with water, and dried. A crude product (7.43 g) was obtained. When this product was recrystallized from a mixture of ethanol and water (1:1), mp183
N,N′-dicyano-N″-[2-(5-
Methylimidazol-4-ylmethylthio)ethyl]guanidine (5.17 g) is obtained. Yield 49.2
%. Elemental analysis: C ₁₀ H ₁₃ N ₇ S Calculated values: C45.61, H4.98, N37.24, S12, 18 Experimental values: C45.59, H4.99, N36.51, S12.17 IR (Nujiol) νmax: 3330, 3110, 2660, 2170, 1575,
1518, 1435, 1378, 1348, 1310, 1230, 867cm
^-1 NMR (DMSO-d ₆ + D ₂ O) δ: 2.32 (3H, s), 2.4-2.7 (2H, m), 3.26 (2H, t, J = 7Hz), 3.83 (2H, s), 8.77 ( 1H,s) (2) N,N′-dicyano-N″-[2-
(5-Methylimidazol-4-ylmethylthio)ethyl]guanidine (527 mg) was added to an ethanolic solution of methylamine (40%, 3.1 g),
Stir at room temperature for 47 hours. The reaction solution was concentrated under reduced pressure, and the residue was triturated with acetonitrile. Undissolved starting material is filtered off and the filtrate is concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a mixture of acetonitrile and methanol (4:
Elute with 1). The eluate was concentrated under reduced pressure, and the concentrated solution was subjected to silica gel thin layer chromatography [developing solvent: a mixture of ethyl acetate, methanol, and 28% aqueous ammonia (10:1:1)], and then reconcentrated from acetonitrile. When crystallized, mp135~137
°C N″-cyano-N-methyl-N′-[2-(5
-methylimidazol-4-ylmethylthio)
Obtain ethyl]guanidine (1.0 mg). Example 2 (1) A chloroform solution (20 ml) of 2-(5-methylimidazol-4-ylmethylthio)ethyl isothiocyanate (prepared from its hydrochloride) (4.17 g) was mixed with cyanamide (1.05 g) and 1,
Chloroform solution (50 ml) of 5-diazabicyclo[5,4,0]-5-undecene (3.80 g)
and stir overnight. After concentrating the reaction solution, the residue was dissolved in water (30 ml), washed with ether, treated with activated carbon, and then diluted to pH5 with 10% hydrochloric acid under ice cooling.
Adjust to. When the precipitate is collected by filtration, washed with water and dried, N-cyano-N'-[2-
(5-Methylimidazole-4-isolmethylthio)ethyl]thiourea monohydrate (3.57g)
get. Elemental analysis: C ₉ H ₁₃ N ₅ S ₂・H ₂ O Calculated values: C39.54, H5.53, N25.62, S23.46 Experimental values: C39.71, H5.44, N25.69, S22. 73 IR (nujiyor) νmax: 3400, 3270, 3130, 2760, 2650,
2190, 1652, 1540, 1470, 1430, 1381, 1362,
1278, 1237, 1217, 1205, 1103, 1088, 967,
837cm ^-1 NMR (DMSO-d ₆ + D ₂ O) δ: 2.32 (3H, s), 2.4-2.8 (2H, m), 3.0-3.67 (2H, m), 3.87 (2H, s), 8.93 (1H ,s) (2) A methylene chloride solution (7 ml) of the monohydrate (765 mg) of N-cyano-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]thiourea obtained above After introducing dry hydrogen chloride gas for several minutes under ice-cooling, phosphorus pentachloride (1.25 g) was added, and the mixture was stirred at room temperature for 3 hours. N″-cyano-
The reaction mixture containing N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]chloroformamidine was concentrated, and the concentrate was diluted with methylene chloride (5 ml) and cooled to -5°C. Add an ethanol solution of methylamine (40%, 15 ml) to this at below 30°C, and stir at room temperature for 20 hours. The reaction mixture is filtered and the filtrate is concentrated. Dilute the concentrate with acetonitrile,
Filter again. The filtrate was concentrated to dryness, and the residue was subjected to column chromatography [silica gel/acetonitrile/methanol (4:1)], and then thin layer chromatography [silica gel/developing solvent: ethyl acetate/methanol/28% ammonia] water (10:1:1)] and then recrystallized from acetonitrile, mp136.5 ~
N″-cyano-N-methyl-N′-[2-
(5-Methylimidazol-4-ylmethylthio)ethyl]guanidine (10.4 mg) is obtained. Yield 1.5%.

Claims (1)

[Claims] 1 General formula [Formula] [In the formula, R ¹ is a lower alkyl group, R ² and R ³ are lower alkylene groups, and X ¹ is a halogen or cyanamide group] ^A compound represented by the formula R ^{4 −NH} ₂ (wherein R ⁴ means ^a lower alkyl group) is reacted with ^the general formula A method for producing an imidazole derivative, characterized by obtaining an imidazole derivative represented by