JPS58170766A - Preparation of n-substituted imidazole - Google Patents

Abstract

PURPOSE:To prepare the titled compound having antibacterial activity, in high yield and purity, from chemically stable raw materials, without necessitating particular consideration to the hygienic control of the work room, by reacting a triphenylmethanol compound with imidazole in the presence of chlorosulfonic acid. CONSTITUTION:The titled compound is prepared by reacting a triphenylmethanol compound with imidazole in the presence of chlorosulfonic acid or fluorosulfonic acid in an inert organic solvent at -50-+140 deg.C, preferably -20- -80 deg.C if necessary in the presence of an acid acceptor. The amount of the chlorosulfonic acid or fluorosulfonic acid is preferably 0.5-5pts.wt. per 1pt.wt. of the triphenylmethanol compound used as a raw material. The inert organic solvent used as the reaction solvent is preferably methylene chloride, dichloroethane, chloroform, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing l-triphenylmethylimidazole, which is characterized by reacting triphenylmethanol and imidazole in the presence of chlorosulfonic acid or fluorosulfonic acid.

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 of substituted phenyl groups include lower alkyl groups such as propyl, alkoxy groups such as methoxy, ethoxy, and propoxy, and aryol groups; specific substituted phenyl groups include m-methylphenyl, 0-chlorophenyl, P-methoxyphenyl, and p-nitrophenyl. etc. can be mentioned.

The 1-triphenylmethylimidazole obtained in this book** is known to have antibacterial properties (
Che-, Bar, 93 P, 576 (196
G) ;Special Publication No. 18752/1975, Special Publication No. 18752
-20015 Publication).

Conventionally, various methods have been known as methods for producing 1-triphenylmethylimidazoles. That is,
(A)) A method of reacting riffle methyl halides with imidazolized botanicals (for example, at 1848-153
No. 07; Japanese Patent Publication No. 18752, 1977; Japanese Patent Publication No. 15, 1972
No. 1970; JP-A-54-17741).

(B) Triphenylmethanols and imidazole or activated imidazole compounds, such as tri(l)
A method of reacting with -imidazolyl)phosphine, venter(1-imidazolyl)phosphorane or imidazole magnesium halide (for example, III# Kosho 4
7-20015; Japanese Patent Publication No. 47-32982; Japanese Patent Publication No. 157561-1987; Japanese Patent Publication No. 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 (Tokusho 55-6206
No. 7; JP-A No. 55-62068) is known.

However, the method (A) uses halide as a raw material and is stable in handling. In addition, it has a rating of 8, which 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, it generally requires a high price. On the other hand, converting imidazole into an active derivative requires complicated operations. Even when a reaction accelerator is added, the reaction temperature is high.

Moreover, in addition to the target product 1-) rifyle methylimidazole, one by-product is produced, and the purification yield is low.

For these reasons, there has been a desire for the development of an easy-to-implement, high-yield method that uses chemically stable raw materials and does not require special considerations for factory hygiene control.

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

To develop a method 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 triphenylmethanol with chlorosulfonic acid or fluorosulfonic acid in an inert organic solvent, and then reacting with imidazole, high-quality 1-triphenylmethylimidazole can be easily produced with good yield. The present invention was completed based on this knowledge.

The present invention will be explained in more detail below.

In the present invention, triphenylmethanol is dissolved in an inert organic solvent, and chlorosulfonic acid or fluorosulfonic acid is added. Then imidazole is reacted. At this time, if necessary, the reaction may be carried out in the presence of an acid binder.

The amount of chlorosulfonic acid or fluorosulfonic acid to be used can be arbitrarily selected depending on the solvent or the reaction temperature, but is preferably 0.5 to 5 times the weight of the raw material triphenylmethanol.

As the inert organic solvent used as the reaction solvent, methylene chloride, dichloroethane, chloroform, trichloroethane, trichlene, etc. are industrially advantageously used. A preferred acid binder optionally used in the reaction is imidazole in excess.

The reaction temperature varies depending on the w chain of the reaction solvent or the amount of chlorosulfonic acid or fluorosulfonic acid used, but -50
The temperature can be selected within the range of 140°C to 140°C, but preferably -20°C to -80°C.

When the target substance, 1-triphenylmethylimidazole, is obtained from the reaction solution thus obtained, it can be obtained, for example, by the Tsuze method.

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-triphenylmethylimidazole 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゜Methylene chloride 450+1 to triphenylmethanol 5.
21 g (0.02 mol) was dissolved at room temperature, 2.80 g of chlorosulfonic acid was added, and then 6.8 g of imidazole was dissolved in □.
1 g (0.1 mol) was added and reacted for 15 minutes. After the reaction was completed, the organic layer was washed with 50-1 of water and separated, the organic layer was distilled off under reduced pressure, and 45 μl of ethanol was added to the residue. crystallize. After filtration and washing with water 1-) Liphenylmethylimidazole 4
．． 66 g are obtained (yield 75.1%). If the obtained crystals are recrystallized with ethanol, s, p, 226°C (literature,
1-triphenylmethylimidazole with a value of 226-227 DEG C.) is obtained.

Elemental analysis value C'-'HN Calculated value 85.13% 5.84% 9.02%
Actual value 85.08% 5.80% 8.99%
Example 2 In the same manner as in Example 1, 5.90 g (0.02 mol) of 0-chlorophenyldiphenylmethanol was used instead of triphenylmethanol. After completion of the reaction, the mixture was washed with 501 ml of water and separated. Thereafter, the organic layer was distilled off under reduced pressure, and 20-1 of acetonitrile was added to the residue for crystallization. After filtering and washing with water, 4.97 g of 1-(0-chlorophenyldiphenylmethylcoimidazole) is obtained (yield 72.1%)
, If the obtained crystals are recrystallized with ethanol, −, p,
142-143°C (literature value 142-145°C)
0-chlorophenyldiphenylmethylcoimidazole is obtained.

Elemental analysis value CHN Calculated value 76.63% 4.97% 8.12%
Actual value 76.57% 4.90% 8.02%
Experimental Example 3゜In the same manner as in Example 1, 2.60 g of fluorosulfonic acid was used instead of chlorosulfonic acid.
After the reaction, the precipitated imidazole salt was filtered off, and the filtrate was subjected to high-performance liquid chromatography to confirm 1-triphenylmethylimidazole, and the production yield was determined using a standard product of 1-triphenylmethylimidazole. Determine using the calibration curve. As a result, the production rate of 1-triphenylmethylimidazole was 89%, and the production yield was 92.7%.

Measurement conditions for high performance liquid chromatography Column: Trupax CN-4,6 x 251 Mobile phase: Acetate buffer (pH 4,8) 500ml + methanol 4501+
Acetonitrile 250 ml Mobile phase flow rate: 1 ml/min Detection method: UV 254 nm Procedural amendment May 2, 1980 Commissioner of the Patent Office 1, Indication of case 1982 Patent layer No. 53244 2, Title of the invention N- Manufacturing method for 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 (+02) Kyowa Hakko Kogyo Co., Ltd. Invention as described in the specification Column 5 of Detailed Explanation, Contents of Amendment As shown in the attached sheet (1) "Chlorsulfonic acid" in the following part of the specification is corrected to "chlorosulfonic acid".

w page 41 line 12 2nd line from the bottom of page 3 Page 4, lines 7-8, lines 3-2 from the bottom Page 5, lines 17-18 Page 7, line 2 (2) Line 1 of page 5 of the specification Correct "~-80℃" to "~+80℃".

Claims (1)

[Claims] A method for producing 1-triphenylmethylimidazole, which comprises reacting triphenylmethanol and imidazole in the presence of chlorosulfonic acid or fluorosulfonic acid.