JPS622591B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing imidazole compounds, more specifically, N-cyano-N′-methyl-N″-{2-[(4-methyl-5-imidazolyl)-methylthio]-ethyl}
The present invention relates to a method for producing guanidine (cimetidine).

The compound represented by the above formula is histamine
It is a useful drug (generic name: cimetidine) that has an H ₂ receptor blocking effect, and is used clinically especially as an anti-ulcer treatment.

Conventionally, N-cyano- expressed by the formula
As a method for producing N′-methyl-N″-{2-[(4-methyl-5-imidazolyl)-methylthio]-ethyl}guanidine, various methods (for example,
No. 2657, No. 56-127361 or Patent Publication 1983-
500026 etc.) are known. However, these known methods involve many reaction routes, require complicated reaction conditions, and use expensive reagents during the reaction, which are economically disadvantageous and are therefore industrially inappropriate.

The inventors of the present invention have conducted various studies to solve the above-mentioned drawbacks, and as a result, they have discovered a new and original method that is highly economical as described below, and have completed the present invention. That is, the general formula (where M is
Alkali metals such as Na, K, Ca, Mg and
(indicating metals such as Zn).

4-Methyl-5-(metalloid thio)methylimidazole and the general formula (wherein R represents halogen, OMs and OTs).

N-cyano-N'-methyl-N''-(2
-substituted ethyl)-guanidine derivative in isopropyl alcohol in the presence of a crown ether, N-cyano-N′-methyl-N″-
The present invention relates to a method for producing {2-[(4-methyl-5-imidazolyl)methylthio]-ethyl}guanidine (cimetidine).

Furthermore, it is a feature of the method of the present invention that when isopropyl alcohol is used as the organic solvent in the above reaction, polymorphic crystals of cimetidine A can be produced directly after the reaction is completed. Conventionally, various crystal forms of cimetidine have been known, and among these, the polymorphic crystal of cimetidine A is said to be the crystal most suitable for actual clinical use. In order to obtain this crystal, for example, JP-A-53-40771 and JP-A-56-104868 have been reported. However, the method of the present invention is very advantageous in that cimetidine A polymorphic crystals can be directly obtained without the need for these crystal form conversions.

According to the method of the present invention, by simply treating 1 mol of the above compound and 1 mol of the compound in the presence of an appropriate amount (0.01 mol to 1 mol) of crown ether in an organic solvent, the method can be easily and quantitatively determined. The desired compound can be produced automatically. Crown ethers include 15-crown-5, benzo-15-crown-5, 18-crown-6, dicyclohexyl-18
-crown-6, dibenzo-18-crown-6,
Dibenzo-24-crown-8, dicyclohexyl-24-crown-8, 21-crown-7, and bicyclic diamino polyether can be used. It is extremely convenient that this crown ether can be recovered and reused after the reaction.

Common organic solvents such as benzene, toluene, xylene, acetonitrile, benzonitrile, methanol, and DMSO can be used, but when isopropyl alcohol is used in the reaction as described above, cytimedine A polymorph crystals are ultimately obtained. It is useful. The reaction proceeds simply by stirring at room temperature, but in order to hasten the completion of the reaction, it is recommended to reflux or heat the solvent below the boiling point of the solvent (80° to 100°C) for a very short time (5 to 6 minutes). The catalytic effect of crown ethers can be explained as follows. That is, S
-The metal of the metal compound () is easily captured by the crown ether, and the remainder becomes an activated anion (S-residue) and is therefore easily combined with other compounds. Crown ether can be quantitatively recovered after the reaction is completed.

EXAMPLES Hereinafter, the present invention will be explained in more detail by showing examples.

<Example 1> 5.6 g of 4-methyl-5-(potassium thio)methyl-imidazole and 8.7 g of N-cyano-N'-methyl-N''-(2-chloroethyl)-guanidine
were added to 80 ml of isopropyl alcohol, and then dicyclohexyl-18-crown-6 0.5
g was added and the mixture was refluxed for 5 minutes. Then,
10 to 20 ml of isopropyl alcohol was directly distilled off from this reaction solution, and the reaction solution was allowed to stand still. The precipitated crystals were over-dried to obtain 8.28 g of polymorphic crystals of pure cytimedine A (mp. 142-143°C).

The cimetidine A solution was further concentrated to recover 0.49 g of dicyclohexyl-18-crown-6. The amount of isopropyl alcohol recovered was 75 ml.

The infrared absorption spectrum (KBr) of cimetidine A obtained in this experiment showed very strong and broad peaks at 1400 cm ^-1 and 1385 cm ^-1 , a strong and sharp peak at 1205 cm ^-1 , and a moderate peak at 1155 cm ^-1 . Although a sharp peak of moderate intensity was observed, no peak was observed at 1180 cm ^-1 .

Elemental analysis value: C ₁₀ H ₁₆ SN ₆ Calculated value (%): C, 47.60; H, 6.39; N,
33.30; S, 12.71; Experimental value (%): C, 47.65; H, 6.42; N,
33.24; S, 12.88. Furthermore, the above experiment was carried out in 80 ml of acetonitrile, and after the same treatment, 8.2 g of cimetidine was added.
(mp. 141-143°C) was obtained.

<Example 2> 4-Methyl-5-(sodium thio)methyl-
Imidazole 5.0g, N-cyano-N'-methyl-
8.7 g of N″-(2-chloroethyl)-guanidine, 80 ml of isopropyl alcohol and 18-crown-
6. After reaction treatment in the same manner as in Example 1 using 0.5 g, polymorphic crystals of pure cimetidine A (mp.142
-143°C) 8.26g was obtained.

This product showed the same infrared absorption spectrum as that obtained in Example 1, and showed no drop in melting point even when mixed.

<Example 3> 4-Methyl-5-(lithium thio)methyl-
4.5 g of imidazole, N-cyano-N'-methyl-
After reacting and treating in the same manner as in Example 1 using 6.8 g of N''-(2-bromoethyl)-guanidine, 0.5 g of cyclohexyl-15-crown-5, and 80 ml of isopropyl alcohol, 8.23 g of polymorphic crystals of pure cytimedine A were prepared. The infrared absorption spectrum of this product was the same as that obtained in Example 1, and it was mixed and did not show a drop in melting point.

<Example 4> 6.5 g of 4-methyl-5-(zincthio)methyl-imidazole, N-cyano-N'-methyl-N''-
A mixture of 6.8 g of (2-bromoethyl)-guanidine, 0.5 g of dibenzo-24-crown-8, and 80 ml of isopropyl alcohol was reacted in the same manner as in Example 1.
After treatment, polymorphic crystals of pure cimetidine A8.21
g (mp. 142-143°C) was obtained. The infrared absorption spectrum of this product was the same as that of the product obtained in Example 1, and it was mixed and did not exhibit a drop in melting point.

<Example 5> 4-Methyl-5-(sodium thio)methyl-
Imidazole 5.0g, N-cyano-N'-methyl-
A mixture of 8.4 g of N″(2-iodoethyl)-guanidine, 0.5 g of dicyclohexyl-18-crown-6, and 80 ml of isopropyl alcohol was reacted and treated in the same manner as in Example 1, and then 8.22 g of polymorphic crystals of pure cimetidine A were obtained. (mp. 142-143°C) was obtained.

The infrared absorption spectrum of this product is Example 1
It was the same as that obtained in 1, and showed no drop in melting point even during blending.

<Example 6> 5.6 g of 4-methyl-5-(potassium thio)methyl-imidazole, 11.2 g of N-cyano-N'-methyl-N''-(2-mesyloxyethyl)-guanidine, dicyclohexyl-18-crown -6
A mixture of 0.5 g and 80 ml of isopropyl alcohol was reacted and treated in the same manner as in Example 1 to obtain 8.25 g (mp. 142-143° C.) of pure cimetidine A crystals.

The infrared absorption spectrum of this product is Example 1
It was the same as that obtained in , and showed no drop in melting point even though it was mixed.

Furthermore, the above reaction was carried out using 80 ml of butyronitrile.
After the same treatment, 8.2 g of cimetidine (mp. 141-143°C) was obtained.

<Example 7> 5.6 g of 4-methyl-5-(potassium thio)methyl-imidazole, 9.5 g of N-cyano-N'-methyl-N''-(2-tosyloxyethyl)-guanidine, dicyclohexyl-18-crown -6
After reacting and treating a mixture of 0.5 g and 80 ml of isopropyl alcohol in the same manner as in Example 1, 8.24 g of pure cimetidine A crystals (mp.142-143
°C) was obtained.

The infrared absorption spectrum of this product is Example 1
It was the same as that obtained in step 1, and it was mixed and did not show any drop in melting point.

Claims (1)

[Claims] 1. General formula (In the formula, M represents an alkali metal and an alkaline earth metal.) 4-Methyl-5-(metalloidthio)methyl-imidazole represented by the general formula N-cyano-N'-methyl-N''-(2
-substituted ethyl)-guanidine derivative in isopropyl alcohol in the presence of a crown ether, N-cyano-N′-methyl-N″-
A method for producing {2-[(4-methyl-5-imidazolyl)methylthio]-ethyl}guanidine (cimetidine).