JPH03218374A - Production of imidazole derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an intermediate of a therapeutic agent for glaucoma, etc., on an industrial scale at a low cost in high yield by reacting an aminoketone derivative with an isothiocyanate derivative in a non-aqueous solvent in the presence of a base and cyclizing the reaction product with an acid catalyst. CONSTITUTION:The objective imidazole derivative of formula III can be produced by reacting an aminoketone derivative of formula I with an isothiocyanate derivative of formula II (R is lower alkyl) in a non-aqueous solvent (e.g. diethyl ether, THF, dioxane and diethoxyethane) in the presence of a base (e.g. sodium ethoxide or triethylamine) and cyclizing the reaction product with an acid catalyst (e.g. HCl, H2SO4, nitric acid or formic acid).

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides a compound of the general formula (III) Hl{ (wherein R is a lower The purpose of the present invention is to provide an industrially advantageous method for producing imidazole derivatives represented by (representing an alkyl group).

According to the present invention, the target compound of formula (II[) is obtained by combining an aminoketone derivative of formula (I) HH with a general formula (I[)RN] in the presence of a base in a non-aqueous solvent.
CS ・・・・・・(I[) (in the formula,
R represents a lower alkyl group) After reacting with an isothiocyanate derivative represented by the formula (R represents a lower alkyl group), the compound is easily produced in a high yield by carrying out a reflux reaction using an acid catalyst.

[Conventional technology]

In the present invention, among the aminoketone derivative (1) and isothiocyanate derivative (II) used as starting materials and the target aminoketone derivative (III), the compound in which R is a methyl group is tetrahedron (Tetrahedron).
hedron) Volume 28, Page 967 (1972),
Journal of Pharmaceutica
l Sciences. Volume 64, page 1700 (
(1975).

This document describes that an imidazole derivative (I) is obtained by cyclizing an aminoketone derivative <1> and an inthiocyanate derivative (II) in a mixed solvent of water and tetrahydrofuran.
A method for producing the compound with a yield of 43% is also described. However, this conventional method is not satisfactory in terms of yield, and the development of an even better method has been awaited.

[Problem to be solved by the invention]

The present invention provides a method for converting the above-mentioned aminoketone derivative (1) and isothiocyanate derivative (I[) into an imidazole derivative (I) through a cyclization reaction, by selecting a reaction solvent to achieve a high yield. The purpose is to establish an industrially advantageous method for producing the target compound.

[Means to solve the problem]

As a result of various studies on various reaction solvents, the present inventors surprisingly found that the reaction yield was dramatically improved by using a non-aqueous solvent, and they were able to complete the present invention. It was.

That is, the present invention provides an aminoketone derivative represented by the formula (I) H}I and the general formula (II) RN in the presence of a base in a non-aqueous solvent.
CS ...... (In) (in the formula, R represents a lower alkyl group) A general method characterized by reacting with an isothiocyanate derivative represented by the following formula, followed by a reflux reaction with an acid catalyst. This is a method for producing an imidazole derivative represented by the formula (DI) HH (wherein R has the same meaning as above).

In carrying out the present invention, the aminoketone derivative (I) and isothiocyanate derivative (II) used as starting materials are known substances, such as Tetrahedr
on, 28, 967 (1972). Journey
of Pharmaceutical Science
ces, 64. 1700 (1975).

Examples of non-aqueous solvents that can be used in the present invention include ethers such as diethyl ether, tetrahydrofuran, dioxane, diethoxyethane, and dimethyl cellosolve, and alcohols such as methanol, ethanol, and i-probanol. , halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane; nitrites such as acetonitrile and probioxynitrile; esters such as ethyl acetate and butyl acetate; and aromatic carbons such as benzene, toluene, and xylene. Examples include amides of hydrogen, formamide, dimethylformamide, and N-methylpyrrolidone, and preferably tetrahydrofuran, i-propanol, chloroform, acetonitrile, ethyl acetate, toluene, and dimethylformamide can be used. .

Examples of the base used in the present invention include metal alkoxides such as sodium ethoxide and potassium t-butoxide, aliphatic amines such as triethylamine and n-propylamine, aromatic amines such as aniline and pendylamine, pyridine, dimethylaminopyridine, etc. Among them, potassium t-butoxide and triethylamine are particularly preferred.

Examples of the acid catalyst used in the present invention include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, organic carboxylic acids such as formic acid, acetic acid, and propionic acid, and organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid. Preferably, sulfuric acid, acetic acid, p-toluenesulfonic acid, etc. can be used.

The aminoketone derivative (I) as a starting material can also be used in the form of a salt such as a hydrochloride.

In carrying out the cyclization reaction in the present invention, the inthiocyanate derivative (I) is used in a molar amount of 0.9 to 5 times, preferably 1 to 3 times the mole of the aminoketone derivative (I) as a starting material, and the base is 0. .1 to 5 times the mole, preferably 1 to 5 times the mole
3 times the molar amount was used, and the acid catalyst was 0. 1 to 1 mole, preferably 0.02 to 0.1 mole, and the solvent is 1 O to 10 mole.
00 times by weight, preferably 20 to 300 times by weight.

The reaction temperature is -30 to 100°C, preferably 20 to 70°C.
The treatment is carried out for 10 minutes to 10 hours, preferably 30 minutes to 5 hours. After the reaction is complete, it can be separated and purified using conventional methods.
The desired imidazole derivative (I) is obtained.

〔Example〕

Examples are shown below to explain the present invention in more detail.

Note that the following examples relate to examples of producing compounds in which R in general formula (I) is a methyl group, but the present invention also applies to cases where R is any lower alkyl group, such as an ethyl group, a probyl group, a butyl group, etc. It is inclusive.

Example 1 1.25 g of hydrochloride of aminoketone derivative (I) and 0.41 g of methyl isothiocyanate were dissolved in 20 ml of chloroform.
The mixture was stirred for 5 minutes at room temperature.

Triethylamine was added to this solution. 85 g was added dropwise over 2 minutes, and the mixture was stirred at room temperature for 1 hour, then heated to 80°C and further stirred for 1 hour.

After the reaction was completed, 3 ml of acetic acid was added to make the mixture acidic, and then 10 ml of saturated saline was added, shaken, and allowed to stand to collect the chloroform layer.

The aqueous layer was further extracted with 10 layers of chloroform, and the extract was combined with the chloroform layer and dried over anhydrous sodium sulfate.

The sodium sulfate in the chloroform layer was filtered off, and the chloroform layer was concentrated. 10 ml of acetic acid was added to the obtained residue, and the mixture was stirred at room temperature for 3 hours.

After distilling off the acetic acid under reduced pressure, isobrobyl alcohol 1
0 ml was added and the solvent was distilled off again under reduced pressure.

The obtained solid was slurried with 5 ml of isopropyl alcohol to obtain 0.90 g (yield: 67%) of the target d-2-mercabutovirocarpine. Melting point: 261-2
64'C. Example 2 A reaction was carried out under the same conditions as in Example 1 except that tetrahydrofuran was used instead of chloroform, and 0.92 g (yield: 68%) of d-2-mercabutopicarbin was obtained.

Example 3 An experiment was carried out in the same manner as in Example 1, except that triethylamine was added dropwise over 1 hour, and 0.84 g (yield: 62%) of the target compound was obtained.

9 Example 4 The reaction was carried out under the same conditions as in Example 1 except that dichloroethane was used instead of chloroform, and 0.90 g of the target product was
(yield: 67%).

Example 5 A solution of 2.72 g (36.09 mmol) of methyl isothiocyanate in 40 ml of isopropanol was placed in a 100 ml eggplant-shaped flask, followed by 2.2 g of triethylamine.
0 g (21.65 mmol) was added. While stirring this solution at room temperature, 4.00 g of aminoketone hydrochloride (1
8.04 mmol) was added portionwise over 2 hours.

After the addition was complete, stirring was continued for an additional 30 minutes. Add 1.4 mj of dilute sulfuric acid (0.2 g of concentrated H2SO4/1 ml of water) to this solution.
After stirring at room temperature for 1 hour, the reaction solution was cooled to 5°C and further stirred for 30 minutes. The precipitated crystals were filtered with suction. The obtained solid was washed with isopropanol (4r
nl×2) L and then water (4 ml×2).

When dried under reduced pressure (10 mmHg) at room temperature, mercaptopilocarpine forms white to pale yellow crystals. 74
g (yield: 63%).

10 [Effect of the invention] The aminoketone derivative (I) and the isothiocyanate derivative (I[) are cyclized to form an imidazole derivative (II).
Regarding the method for producing I), a method was conventionally known in which the target compound was obtained in a yield of 43% by reacting in a mixed solvent of water and tetrahydrofuran, but according to the present invention, the target compound was obtained in a yield of 6.
A new manufacturing method capable of producing the desired product with a yield of 2 to 68% was provided.

Claims (1)

[Claims] In the presence of a base in a non-aqueous solvent, formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・(
I) Aminoketone derivative represented by general formula (II) RNC
A general method characterized by reacting with an isothiocyanate derivative represented by S...(II) (in the formula, R represents a lower alkyl group) and then carrying out a reflux reaction with an acid catalyst. Formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・(I
II) A method for producing an imidazole derivative represented by (wherein R has the same meaning as above).