JPS5938949B2 - Method for producing N↓-substituted imidazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 1-triphenylmethylimidazoles, which is characterized by reacting tri-(1-imidazolyl)-phosphines and triphenmethanols.

Examples of tri-(1-imidazolyl)-phosphines include those of the general formula (1) P(-NゝR2)3(1) W゛ (wherein R1, R2 and R3 are the same or different hydrogen atoms, lower alkyl group, lower alkenyl group, aryal group,
Indicates a cyano group, lower alkoxy group, nitro group, lower alkoxycarbonyl group, lower alkylamino group, and halogen atom.

) Tri-(1-imidazolyl)-phosphines represented by:

In the above formula, lower refers to 1 to 8 carbon atoms. Triphenylmethanol used in this reaction means triphenylmethanol having a substituted or unsubstituted phenyl group.

Examples of the substituted phenyl group include phenyl groups substituted with a nitro group, a halogen atom, an alkoxy group, a lower alkyl group, and an aryl group. Examples include enyl, metamethylphenyl and biphenyl groups, but are not particularly limited thereto. The 1-triphenylmethylimidazole obtained by the present invention includes, for example, 1-triphenyl obtained by reacting the tri-(1-imidazolyl)-phosphine of the general formula (1) with the triphenylmethanol. Examples include methylimidazole.

1-Triphenylmethylimidazole obtained by the present invention is a known compound and is already known to exhibit antibacterial activity [Chem. Ber. , vol. 92, p. 92 (
1959); Chem. Ber. , vol. 93, p. 570 (1960); Chem. Ber. , vol. 93, 576
Page (1960); Japanese Patent Publication No. 18752/1983].

These known production methods involve reacting triphenylmethyl halides with silver or sodium salts of imidazoles, but these methods have a series of drawbacks. For example, silver salts of imidazoles lack stability against light, and furthermore, they are very expensive raw materials. On the other hand, triphenylmethyl halides are unstable in water and susceptible to hydrolysis. Moreover, these known production methods have the disadvantage of a low yield of 50% or less. The triphenylmethyl halides used in this method can generally be prepared from triphenylmethanols. Therefore, when triphenylmethanols are used as a starting material to produce 1-triphenylmethylimidazoles, there is a great industrial advantage in that the step of producing triphenylmethyl halides can be omitted. From the above point of view, an improved production method in which triphenylmethanols and imidazoles are reacted has been investigated.

For example, triphenylmethanols and imidazoles are 1
1-Triphenylimidazoles can be produced by heating at a temperature of 40 to 230°C (Japanese Patent Publication No. 47-2
Publication No. 0015). This method has the industrial advantage of not using triphenylmethyl halides, but on the other hand, it uses inert triphenylmethanols, so it does not require high temperatures, which is an industrial disadvantage. It has disadvantages that cannot be avoided.

In this way, triphenylmethanols are generally more inert than triphenylmethyl halides, and therefore have significantly less reactivity.Therefore, when carrying out reactions at industrially advantageous temperatures, imidazoles must be activated. Therefore, when triphenylmethanol is used as a raw material, the reaction is limited and only two methods are currently known. Most of the numerous known production methods of the same type use triphenylmethyl halides as starting materials.Currently, the only known method using active derivatives of imidazoles is thionyl imidazolide [ATln. , Vol. 694, p. 86 (1966)] or carbonyldiimidazole [A
rzneimFOrschl22, Black 8 (1972)]
This is the reaction between
61522). During research on the synthesis of organophosphorus compounds, the present inventors found that tri-(1-imidazolyl)-phosphines react more easily with triphenylmethanols, and 1-
It was discovered for the first time that triphenylmethylimidazoles were formed.

The characteristics of the method of the present invention are not only the industrial advantages of using triphenylmethanol as a raw material, but also the fact that the reaction can proceed satisfactorily without requiring industrially disadvantageous high temperatures. can give.

Furthermore, since the reaction proceeds even in the presence of a small amount of solvent, the volumetric efficiency of the reaction increases, and the reaction proceeds in a short time even at temperatures below 100'C.
Compared to conventional methods, this method has significant industrial advantages, such as the fact that the reaction time is greatly shortened and the target compound can be obtained in good yield. To explain the method of the present invention in more detail, tri-(1-imidazolyl)-phosphines are produced by the reaction of trialkylsilyl imidazoles with phosphorus trichloride (AIlgeW.Chem.
, 73, 143 (1961)).

Alternatively, it can be produced by reacting phosphorus trichloride with an imidazole containing unsubstituted nitrogen atoms in an amount of 3 or more moles relative to phosphorus trichloride in the presence of an acid binder. As the acid binder, a base that does not interfere with the reaction is usually used, but it is particularly preferable to use a tertiary organic amine base such as pyridine or triethylamine or imidazole as a raw material. Examples of solvents include aromatic hydrocarbon compounds such as toluene and benzene, halogenated hydrocarbons such as chloroform or methylene chloride, ether solvents such as tetrahydrofuran, and nitrogen-containing compounds such as pyridine and acetonitrile, but are not particularly limited to these. It's not a thing. Furthermore, since this reaction is an exothermic reaction, it is desirable to cool it. In this reaction, the reaction usually proceeds quantitatively to give tri-(1-imidazolyl)-phosphines. In the reaction of tri-(1-imidazolyl)-phosphines and triphenylmethanols, the tri-(1-imidazolyl) phosphines obtained by the above method do not require particular isolation and purification; Even when triphenylmethanols are added directly to the reaction mixture, the desired 1-triphenylmethylimidazoles can be obtained in good yield.

In this reaction, any solvent can be used as long as it does not interfere with the reaction, and usually acetonitrile, chloroform, etc. can be used. Although the reaction can proceed at room temperature, it may be heated to accelerate the reaction. Further, the tri-(1-imidazolyl)-phosphine used as a raw material is used in an amount of % or more times the mole of triphenylmethanol, preferably % to 2 times the mole. Next, details will be explained using examples.

Example 1 A solution of imidazole 107 and chloroform 50ml
Cool to below 0°C, add 3.4357 phosphorus trichloride dropwise,
After stirring for 1 hour at 5-10°C, the precipitated imidazole hydrochloride is separated, and the solvent of the aqueous solution is concentrated under reduced pressure. To the resulting triimidazolylphosphine solution is added 6.0 mg of triphenylmethanol.
257 was added and heated at 40 to 60°C for 5 minutes, the resulting solid was extracted with chloroform, the extract was washed with water, dried with Glauber's salt, and the solvent was distilled off under reduced pressure to obtain a white solid (yield almost quantitative). ) is recrystallized from a mixed solvent of acetonitrile and chloroform to obtain 7.0y (90%) of 1-triphenylmethylimidazole as colorless needles.

Melting point: 220-22"C Example 2 In the same manner as in Example 1, using o-chlorophenyldiphenylmethanol instead of triphenylmethanol, 1-[0-chlorophenylbisphenylmethyl]
Imidazole was obtained.

Yield 95%. Crystallized from acetonitrile, melting point 140
Crystals at ~142°C were obtained. Yield 84% o Example 3 Tri-(1-imidazolyl)-phosphine 0.997 (4.
3mM) was dissolved in 30ml of chloroform and heated to 0~10°C.
Triphenylmethanol 2.207 (8.5 m
Add M) and stir for 30 minutes.

Water is added to the reaction solution and extracted with chloroform, and the chloroform layer is washed with 5% caustic soda water, further washed with water, and then dried over magnesium sulfate. If chloroform is distilled off under reduced pressure and the remaining crude crystals are recrystallized from acetonitrile, Mp2l9-22
1-Triphenylmethylimidazole showing 0°C 2.1
17 (yield 80.5%) was obtained. Example 4 Imidazole 2.04y, triethylamine 3.337y
and chloroform 50me in a mixture of 1.3
77 was added dropwise over 15 minutes at 0 to 15°C, and after further stirring at the same temperature for 1 hour, 2.67 g of triphenylmethanol was added and the mixture was refluxed for 2 hours.

After the reaction, water was added and thoroughly stirred, the chloroform layer was separated, the chloroform extract was washed with water, and after drying with sodium sulfate, the solvent was distilled off and the resulting white solid was washed with isopropyl ether to yield 3.057 (98.4%) of 1 -Triphenylmethylimidazole is obtained. Recrystallization from acetonitrile yielded pure 1-triphenylmethylimidazole with a melting point of 220-22"C. Example 5 In the same manner as in Example 4, o-chlorophenyldiphenyl diphenyl instead of triphenylmethanol was used. using enylmethanol, 1-[0-chlorophenylbisphenylmethyl]
Imidazole was obtained.

Yield 90% Melting point 140-142°C Example 6 Tri(1-imidazolyl)phosphine 0.99y (4.
Dissolve 3mm01e) in 30ml of chloroform and
o-chlorophenyldiphenylmethanol 2 at 10°C
．． 507 (8.5 mm01e) was added and reacted for 1 hour.

Add water to the reaction solution and extract with chloroform. The chloroform layer is washed successively with 5% caustic soda water and water, and dried over magnesium sulfate. When chloroform is distilled off and the residue is recrystallized from acetonitrile, it shows a melting point of 142-143°C.
-(0chlorophenylbisphenylmethyl)imidazole 2.2y (yield 75%) was obtained. Example Fuimidazole 4.487y, triethylamine 6.96y
and 80d acetonitrile in a mixture of 3.
92y was added dropwise at room temperature, and after further stirring at the same temperature for 1 hour, o-chlorophenyl diphenylmethanol 5.90
Add 7 and reflux for 2 hours.

After cooling, the solvent was distilled off and extracted with chloroform. The chloroform extract was treated in the same manner as in Example 6, and the melting point was 14.
5.727 (yield: 83%) of 1-(0-chlorophenylbisphenylmethyl)imidazole having a temperature of 2 to 143°C was obtained. Example 8 A mixture of 2.247 y (33 mm 01e) of imidazole, 3.03 y (33 mm 01 e) of triethylamine and 40 ml of toluene was added with 1.51 y (11 mm 0
1e) was added dropwise at 50 to 55°C, and further 1e) was added at the same temperature.
After stirring for an hour, 2.957 (0.01 mOle) of o-chlorophenyldiphenylmethanol was added and the mixture was refluxed for 2 hours.

Claims (1)

[Scope of Claims] 1. A method for producing 1-triphenylmethylimidazoles, which comprises reacting tri-(1-imidazolyl)-phosphines and triphenylmethanols. 2. The method according to claim 1, wherein the tri-(1-imidazolyl)-phosphine is tri-(1-imidazolyl)-phosphine. 3. The manufacturing method according to claim 1 or 2, wherein the triphenylmethanol is triphenylmethanol. 4. The manufacturing method according to claim 1 or 2, wherein the triphenylmethanol is halogenophenyldiphenylmethanol. 5. The manufacturing method according to claim 4, wherein the halogenophenyldiphenylmethanol is o-chlorophenyldiphenylmethanol. 6 Claim 1 in which the 1-triphenylmethylimidazole is 1-triphenylmethylimidazole
, 2 or 3. 7. The manufacturing method according to claim 1, 2, 4 or 5, wherein the 1-triphenylmethylimidazole is 1-[halogenophenylbisphenylmethyl]imidazole. 8. The production method according to claim 7, wherein the 1-[halogenophenylbisphenylmethyl]imidazole is 1-[o-chlorophenylbisphenylmethyl]imidazole.