JPH0586948B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to cimetidine (N-cyano-N'-
This invention relates to a novel method for producing methyl-N''-[2-{(5-methyl-1H-imidazol-4-yl)methylthio}ethyl]guanidine) or cimetidine-related compounds. problem,
[Effects of the Invention] Several methods for producing cimetidine or cimetidine-related compounds have been proposed so far (for example, JP-A-49-75574, JP-A-51-
No. 125074, etc.), but these methods use expensive imidazole derivatives as starting materials and are production methods that involve multi-step reactions, so they have the drawback of high costs. The present invention provides a new method for producing imidazole derivatives that eliminates the above-mentioned drawbacks of conventional methods.The present invention is characterized by the use of raw materials that are inexpensive and can be obtained in high yields, and in which the imidazole ring is removed in the final step. The present invention has been improved so that cimetidine or cimetidine-related compounds can be economically obtained by forming the following. [Structure of the invention] That is, the present invention provides the general formula ()

[In the formula, R ¹ represents an acyl group and R ² represents a lower alkyl group. ] by reacting an α-acyloxyketone derivative represented by the formula () with a formic acid derivative and an ammonium salt.

[In the formula, R ² is the same as above. The gist of the present invention is a method for producing an imidazole derivative, which is characterized by obtaining an imidazole derivative represented by the following. In the α-acyloxyketone derivative represented by formula () according to the present invention, examples of the lower aliphatic acyl group used for R ¹ include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, sec
-butyl group, etc., and particularly preferably an acetyl group. Examples of the lower alkyl group for ^R2 include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and isobutyl, with methyl being preferred. The acyloxyketone derivative represented by the formula () has the general formula

[Formula] [In the formula, X is a hydrogen atom, a chlorine atom, or a bromine atom. ] Methyl vinyl ketone derivative and general formula

[In the formula, R ² is a lower alkyl group. ]

The mercaptoguanidine derivative represented by
React with the general formula

〔Example〕

Hereinafter, the method of the present invention will be specifically explained with reference to Examples. Example 1 Production of N-cyano-N′-methyl-N″-[2-{(5-methyl-1H-imidazol-4-yl)methylthio}ethyl]guanidine N-{2-(2-acetoxy-3 -Oxobutylthio)ethyl}-N'-cyano-N''-methylguanidine (155 mg) and methyl orthoformate (290 mg) were dissolved in formamide (2.5 ml), and then 170 mg of ammonium formate was added and stirred at 100°C for 2 hours. After the formamide in the reaction mixture was distilled off under reduced pressure, the residue was isolated and purified by silica gel chromatography (elution solvent: chloroform:methanol = 4:1), and then recrystallized from isopropanol to obtain white crystals. 36 mg of the product was obtained (yield 26%). Examples 2 to 3 When the reaction was carried out in the same manner as in Example 1 except that the ammonium salts listed in Table 1 were used instead of ammonium formate in Example 1, cimetidine was obtained in the yield shown in Table 1.

[Table] Examples 4 to 7 Table 2 was used instead of formamide in Example 1.
When the reaction was carried out in the same manner as in Example 1 except for using the described solvent, cimetidine was obtained in the yield shown in Table 2.

[Table] Examples 8 to 10 When the reaction was carried out in the same manner as in Example 1 except that the formic acid derivatives listed in Table 3 were used instead of methyl orthoformate in Example 1, cimetidine was produced in the yield shown in Table 3. Obtained.

[Table] Example 11 136 mg of N-{2-(2-formyloxy-3-oxobutylthio)ethyl}-N'-cyano-N''-methylguanidine and 530 mg of methyl orthoformate were dissolved in 2.5 ml of formamide, and formic acid Added 320 mg of ammonium and stirred at 100°C for 2 hours. Post-treated in the same manner as in Example 1 to obtain the desired product (cimetidine) 71 as white crystals.
mg (yield 56%). Reference Example 1 Production of N-{2-(2-acetoxy-3-oxobutylthio)ethyl}-N'-cyano-N''-methylguanidine In a 50 ml two-necked flask, N-{2-(2-chloro-
3-oxobutylthio)ethyl}-N'-cyano-
Added 0.64 g of N''-methylguanidine (compound described in Japanese Patent Application No. 61-203640), 10 ml of methanol, and 0.31 g of anhydrous sodium acetate, and stirred at room temperature for 8 hours. Methanol was distilled off under reduced pressure, water was added, and ethyl acetate was added. After drying over anhydrous magnesium sulfate, ethyl acetate was distilled off under reduced pressure to obtain the desired product as a brown liquid.
Obtained 0.57g (yield 83%). ^1H -NMR spectrum ( _CDCl3 -MeOD- _d4 ;
ppm)

[C] (a)or(b) 2.20 (3H, s) (a)or(b) 2.27 (3H, s) (c) 2.80 (2H, m) (d) 2.86 (3H, d, J=5.4 Hz) (e) 3.00 (2H, m) (f) 3.42 (2H, m) (g) 5.26 (1H, dd, J=5.4and7.2Hz) (h) 6.50 to 6.88 (2H, m) Reference example 2 Production of N-(2-formyloxy-3-oxobutylthio)ethyl-N'-cyano-N''-methylguanidine Same as Reference Example 1 except that sodium formate was used instead of anhydrous sodium acetate. The reaction was carried out in the same manner as in Reference Example 1, and the desired product was obtained as a brown liquid (yield: 46%). ¹ H-NMR spectrum (CDCl ₃ -MeOD-d ₄ ;
ppm)

[ka] (a) 2.25 (3H, s) (b) 2.85 (2H, m) (c) 2.90 (3H, d, J = 5.4Hz) (d) 3.00 (2H, m) (e) 3.42 (2H, m) (f) 5.35 (1H, dd, J=5.4and7.2Hz) (g) 6.42~6.84 (2H, m) (h) 8.05 (1H, s)

Claims (1)

[Claims] 1 Formula () [In the formula, R ¹ represents a lower aliphatic acyl group, and R ² represents a lower alkyl group. ] [In the formula, R ² is the same as above. ] A method for producing an imidazole derivative represented by