JPS58216163A - Production of n-substituted imidazole - Google Patents

Abstract

PURPOSE:The reaction between triphenylmethanol and an imidazole unsubstituted in the 1-position is carried out in the presence of nitric anhydride, NO2 or N2O4, thus permitting the high-yield production of the titled compound with antibacterial activity from chemically stable starting materials at relative low temperatures. CONSTITUTION:The reaction between a triphenylmethanol and an imidazole unsubstituted in the 1-position is carried out in a solvent such as methylene chloride or dichloroethane in the presence of nitric anhydride (N2O5), NO2 or N2O4 at -40-100 deg.C to give the objective compound. The amount of nitric anhydride is preferably 0.5-8 times the weight of the triphenylmethanol.

Description

Detailed Description of the Invention The present invention is characterized in that triphenylmethanols and 1-unsubstituted imidazoles are reacted in the presence of anhydrous nitric acid, nitrogen dioxide, dinitrogen tetroxide, or a mixture thereof. -Relating to a method for producing triphenylmethylimidazoles.

The triphenylmethanols include triphenylmethanol having a substituted or unsubstituted phenyl group. As a substituent for a substituted phenyl group.

Halogen atoms such as chlorine and bromine, methyl and ethyl.

Examples include lower alkyl groups such as propyl, alkoxy groups such as methoxy, ethoxy, propoxy, and aryl groups. Specific substituted phenyl groups include m-methylphenyl, 0-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, etc. It will be done.

The 1-triphenylmethylimidazole obtained in the present invention is known to have antibacterial properties (
Ghem, Ber, 93 P, 576 (19
60) ;Special Publication No. 47-18752, Special Publication No. 4
Various methods are known for producing 1-triphenylmethylimidazole. That is, (A
) A method of reacting triphenylmethyl halides with imidazole compounds (for example, Japanese Patent Publication No. 4 B-1530
No. 7; Special Publication No. 47-18752; Japanese Patent Publication No. 159-1973
No. 70; JP-A-54-17741).

(B) Triphenylmethanols and imidazole or an activated imidazole compound, such as tri(1
A method of reacting with -imidazolyl)phosphine, venter(1-imidazolyl)phosphorane or imidazole magnesium halide (for example, Japanese Patent Publication No. 47-2
No. 0015; Japanese Patent Publication No. 1984-32982; Japanese Patent Publication No. 1983-
No. 157561; JP-A-55-2644).

(C) A method in which triphenylmethanols and imidazole are reacted in the presence of a reaction accelerator, such as a phosphorus oxyacid ester.

Titanium chloride, aluminum chloride (for example, JP-A-55-
No. 62067; JP-A-55-62068) is known.

However, in the method (A) above, the raw material is a halide, and the earthwork is stable in handling. However, it has a number one drawback that requires special consideration in terms of hygiene management. (B),
Method (C) has the advantage of not using triphenylmethyl halide as a raw material. However, since the raw material is triphenylmethanol, which is inert compared to halides, high temperatures are generally required. On the other hand, converting imidazole into an active derivative requires complicated operations. Furthermore, even when a reaction accelerator is added, the reaction temperature is high.

Moreover, it has drawbacks such as the production of by-products in addition to the desired product, 1-triphenylmethylimidazole, and a poor purification yield.

For these reasons, industrially, chemically stable raw materials are used and easy methods are used at relatively low temperatures.

Moreover, it was desired to develop a method that could be implemented with good yield.

The present inventors have overcome the drawbacks of the above-mentioned conventional methods.

In order to develop a process for producing 1-triphenylmethylimidazole that can be easily carried out with good yield on an industrial scale.

I did various research.

As a result, by reacting triphenylmeth(3)tanols with anhydrous nitric acid, nitrogen dioxide, dinitrogen tetroxide, or a mixture thereof in an inert organic solvent, triphenylbenium ions can be stably produced.
It was then discovered that high quality 1-triphenylmethylimidazoles can be produced easily and in good yield by reacting with 1-unsubstituted imidazoles. The present invention was completed based on this knowledge.

The present invention will be explained in more detail below.

In the present invention, triphenylmethanols are dissolved in an inert solvent, nitric anhydride (N20s), nitrogen dioxide (NO2), dinitrogen tetroxide (N204) or a mixture thereof is added, and then 1 -Unsubstituted-imidazole is reacted. At this time, if necessary, the reaction may be carried out in the presence of an acid binder.

Anhydrous nitric acid or nitrogen dioxide used in the present invention,
The amount of dinitrogen tetroxide or its mixture to be used can be arbitrarily selected depending on the type of solvent or reaction temperature, but is preferably 0.5% based on the triphenylmethanol starting material.
~8 times the weight is preferred.

As an inert solvent used as a reaction solvent.

Organic solvents such as methylene chloride, dichloroethane, trichloroethane, etc. are used. It is also possible to use liquid sulfite as an inorganic (4) solvent. In the presence of liquid sulfurous acid, the reaction proceeds quickly and with good yield, so it can be used industrially advantageously. A preferred acid binder optionally used in the reaction is imidazole in excess.

The reaction temperature depends on the type of reaction solvent or nitric anhydride.

Although it varies depending on the amount of nitrogen dioxide, dinitrogen tetroxide, or a mixture thereof used, it can be selected in the range of -80°C to 130°C, but preferably -40°C to +100°C.

When obtaining the target substance 1-triphenylmethylimidazole from the reaction solution obtained in this way,
For example, it can be obtained by the method described by Kogi.

The solvent of the reaction solution was distilled off under reduced pressure, water was added to the residue,
The product is then extracted by adding chloroform or methylene chloride. By concentrating the extract,
Crude 1-triphenylmethylimidazoles can be obtained. Next, this material is recrystallized using, for example, acetonitrile.

Alternatively, a highly pure target substance can be obtained by purification by column chromatography or the like.

Examples are shown below.

Example 1゜O-chlorophenyldiphenylmethanol 2.95g
' (0.01 mol) was dissolved in 100 ml of methylene chloride, cooled to -30°C, and dissolved in 15 ml of liquid sulfite. Then 1.0 g of nitrogen dioxide is added. After 1 hour, 3.0 g of imidazole was added and reacted for 1 hour. After the reaction was completed, the precipitated imidazole salt was filtered off and washed with water.

The organic layer is distilled off under reduced pressure. Acetonitrile was added to the residue for crystallization to obtain 1.93 g of 1-[o-chlorophenyldiphenylmethylcoimidazole. (Yield 56
%) This product was recrystallized with ethanol to give a melting point of 142-1
1(0-chlorophenyldiphenylmethylcoimidazole) was obtained at 43°C (literature value 142-145°C).

Elemental analysis value (, HN calculated value 76, 6'3% 4.97% 8.1
2% actual value 76.52% 4.86% 8.0
9% Example 2゜In the same manner as in Example 1, triphenylmethanol 2 was used instead of 0-chlorophenyldiphenylmethanol.
．． 6 g (0.01 mol) are used for the reaction. After the reaction was completed, the precipitated imidazole salt was filtered off, and 1-triphenylmethylimidazole was confirmed in the filtrate by high performance liquid chromatography. The production yield is 1-
It was determined using a calibration curve using a standard product of triphenylmethylimidazole. As a result, the production yield of 1-triphenylmethylimidazole was 83.6%.

Measurement conditions for high performance liquid chromatography Carafe: Solhasous CNφ4.6mm x 25cm Mobile phase: Acetic acid buffer (pH 4,8) 500ml + methanol 450ml
1 + acetonitrile 50 ml Mobile phase flow rate: 1 ml/min Detection method: UV 254 nm Example 3 Dissolve triphenylmethanol 0.26 g (0,001 mol) in methylene chloride 10 ml and add nitric anhydride 0.39 g at room temperature. . After 1 hour imidazole 0.3
Add 0g and react for 1 hour. After the reaction was completed, the precipitated imidazole salt was filtered off, and 1-triphenylmethylimidazole was confirmed in the filtrate by high performance liquid chromatography. The production yield was determined using a calibration curve using a standard product of 1-triphenylmethylimidazole. the result.

(7) The production yield of 1-triphenylmethylimidazole is 86
．． It was 8%.

Patent Applicant (102) Kyowa Hakko Kogyo Co., Ltd. (8) Procedural Amendment March 23, 1982 1. Indication of Case 1982 Patent Application No. 100158 2. Title of Invention Process for producing N-substituted imidazoles 3. Relationship with the case of the person making the amendment Patent applicant Postal code 100 Address 6-1 Otemachi-chome, Chiyoda-ku, Tokyo Name (102) Detailed description of the invention in the specification of Kyowa Hakko Kogyo Co., Ltd. 5. Contents of the amendment As shown in the attached sheet (1) Between the first and second lines of page 2 of the specification [also:
In the 1-unsubstituted imidazoles, the nitrogen atom at position 1 of the imidazole ring is unsubstituted, and the other positions are substituted or unsubstituted imidazole. Examples of the substituent include a halogen atom, a nitro group, a lower alkyl group, an alkoxyl group, and an aryl group. ” Add 6 lines.

(2) On page 6, line 11 of the specification, "Reta. (yield 56%) this thing" was changed to "reta (yield 56%)"
6%). Correct this to "this one."

Claims (1)

[Claims] A method for producing 1-triphenylmethylimidazoles, which comprises reacting triphenylmethanols and 1-unsubstituted imidazoles in the presence of anhydrous nitric acid, nitrogen dioxide, dinitrogen tetroxide, or a mixture thereof.