JPS5888347A - Preparation of azomethine compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a raw material for preparing an antagonist cimetidine, by reacting N-cyano-methylamino-ethyleneimino-azomethine with hydrogen chloride or a hydrogen chloride donor. CONSTITUTION:N-Cyano-methylamino-ethyleneimino-azomethine of formulaIis reacted with hydrogen chloride or a hydrogen chloride donor, e.g. pyridine hydrochloride which is a hydrochloride of an organic tertiary amine, in a solvent, e.g. methanol, chloroform or benzene, at room temperature-50 deg.C, preferably 40-50 deg.C, to give an azomethine compound N-cyano-methylamino-2'-chloroethylamino-azomethine which is the aimed substance of formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an azomethine compound, particularly N-cyano-methylami2-2-chloroethylamino-azomethine represented by the following formula [T1].

CN The above compound [I] is useful as a starting material for the synthesis of cimetidine, which is known as an effective antagonist of histamine at the H2 receptor.

Conventionally, as a method for producing the above compound [I], a method of reacting 2-chloroethylamine and dimethyldicyanimide dithiocarbonate has been proposed (Japanese Patent Publication No. 54
-40547), nothing has been clarified about the physical properties of the resulting compound, and many by-products are produced in addition to the desired product, and furthermore, isolation and purification thereof is extremely difficult. Therefore, if the compound obtained by this method is used to synthesize cimetidine without purification, the yield will be extremely low, making it impossible to industrially produce cimetidine.

The present invention has been made in view of the above, and is a compound characterized by reacting N-cyano-methylamino-ethyleneimino-azomethine represented by the formula LIII with hydrogen chloride or a hydrogen chloride donor in the presence of a solvent. A method for producing [I] is provided.

In general, a method of ring-opening ethyleneimines to form halides is known, but there is no example of compound [I] being derived from ethyleneimines of the formula [■] as in the present invention O. . This is because Compound [I] is extremely unstable to acids and self-reacts in the presence of a base. It was considered extremely difficult to lead to [I]. The present invention was completed after detailed studies on the reaction conditions revealed that the above-mentioned compound [formerly] can be efficiently converted to compound [I] by the action of hydrogen chloride or a hydrogen chloride donor. It is what was done.

As the hydrogen chloride donating agent used in the present invention, hydrochloride of an organic tertiary amine, particularly pyridine hydrochloride, is effective.

Examples of solvents include alcohols (e.g., ethanol, methanol, globanol), halogen-containing solvents (e.g.,
(dichloromethane, chloroform, carbon tetrachloride, etc.), nonpolar solvents (eg, benzene, toluene, n-hexane, etc.), and the most preferred example of the solvent is chloroporm.

The reaction can be carried out at room temperature to about 50'C, but preferably about 40-50'C.

According to the method of the present invention, the compound [old] can be efficiently converted into the target compound [I], and substantially no side reaction products are produced. The isolation and purification of the target compound [I] is easy, and the yield is 80% as shown in the examples below.
reach more than 1.

To illustrate the method for synthesizing cimetidine using the obtained compound [I] as a starting material, the compound [I] and 4(51-methyl-5(4)-mercaptomethylimidazole [111]
Cimetidine [
IV] is obtained in high yield (for example, 80%).

Next, examples of the present invention will be described.

Example 1 Chloroform IOmetfCN-cyano-methylamino-ethyleneimino-azomethine (1)+oomp and pyridine hydrochloride+41! +9: Add ll m9 and heat to 50℃
The temperature rises to After 1 hour, the reaction solution is filtered and the F solution is distilled off. The residue was crystallized from petroleum ether to give the target product, N-cyano-methylamino-2-chloroethylamino-
107 mg of azomethine [I] is obtained. Yield 83%.

Melting point near 6-78℃, Infrared absorption spectrum: See Figure 1.

Example 2 100 mf of N-cyano-methylamino-ethyleneimino-azomethine [II] is added to 10 m4 of ethanol, and the mixture is stirred at 0 to 5°C. Ethereal hydrogen chloride was added to this, and after 10 minutes, the hydrogen chloride was removed without heating, and 5 g of Wakogel C-AOO was added to adsorb the crude product in the reaction stock solution.

By adding a sample of silica gel onto a column prepared with 100F Wakogel C-AOO and subjecting the reaction solution to column chromatography using ethyl acetate as an eluent, the desired N-cyano-methylamino-2-chloro 50 my of etelamisoazomethine [I] is obtained. Yield 38
blood.

The target fraction was Kieselgel 60F2.4 (thickness 0
．． 20) using a thin layer plate [manufactured by Merck & Co., Ltd.] and using ethyl acetate as the developing solution, R, = 0.5 is detected, and FeCe
If a 5% ethanol solvent of 8.6H20 is sprayed and then heated with a dryer, a reddish-yellow color appears.

Melting point near 6-78°C.

Reference example (synthesis of cimetidine) N-cyano-methylamino-2-chloroethylaminoazomethine [I] 65.4fnf, 5(
4)-Methyl-4(5)-mercaptomethylimidazole [11] 67 ml of hydrochloride and 38 ml of sodium hydroxide as a condensing agent were added to 5 wIg of acetone, stirred at room temperature for 3 to 4 hours, and the reaction solution was Forgive.

The P solution is distilled off, and the mixture is extracted with ethyl acetate and a 2N aqueous sodium hydroxide solution. The ethyl acetate phase is treated with sulfur salt and then distilled off. Remove the residue using Merck 60 F254 (thickness 0.25m)
) scrape off with a thin plate. Methanol is used as a developing solution. After extracting the desired product with acetone and distilling off the solvent,
Crystallization from acetonitrile and ether gives cimetidine [N] 78 mli'.

Yield 76%.

Melting point = 139-141℃ Infrared absorption spectrum: Matches the standard.

[Brief explanation of drawings]

FIG. 1 shows an infrared absorption spectrum of compound [I] obtained by the present invention. Patent applicant Fujimoto Pharmaceutical Co., Ltd. Agent Patent attorney Shinhachibe Miyazaki

Claims (3)

[Claims] (1) A method for producing an azomethine compound represented by the formula: % formula %, which comprises reacting a compound represented by the formula: with hydrogen chloride or a hydrogen chloride donor in the presence of a solvent. (2) Hydrogen chloride donor: The method for producing an azomethine compound according to item (1) above, which is a hydrochloride of an organic tertiary amine. (3) The method for producing an azomethine compound according to item (2) above, wherein the hydrochloride of the organic tertiary amine is pyridine hydrochloride.