JP2869566B2 - 2- [1- (2-hydroxyethyl) ethenyl] -1H-imidazole derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a raw material monomer for a polymer material,
The present invention relates to a 2- [1- (2-hydroxyethyl) ethenyl] -1H-imidazole derivative expected to be used as a general industrial chemical and further as an antibacterial agent, and a method for producing the same.

BACKGROUND OF THE INVENTION A 2-ethenyl-1H-imidazole derivative is a compound that is used in a wide range of industrial fields.

For example, 2-ethenyl-1H-imidazole is used as a polymerization monomer of a polymer flocculant used in wastewater treatment of the paper manufacturing industry and the like, and U.S. Pat. The invention of a nickel plating tank using 2-propenyl-1H-imidazole or the like as a brightener for nickel plating is described. U.S. Patent No.
Nos. 4252671 and 4252673 describe the use of 2-vinyl-1H-imidazole as a raw material monomer of a copolymer used as a colloid solution modifier for metal particles.

As described above, since the 2-ethenyl-1H-imidazole derivative is a very useful compound, the appearance of a derivative with higher added value is desired for further development in the field.

On the other hand, it is known that many imidazole derivatives have an antibacterial action. Particularly, those having an excellent action are disclosed in, for example, JP-A-57-81469. Enitel-1H-imidazole derivatives are described, and JP-A-1-250357 discloses 1- (2-hydroxyethyl) -1H having a hydroxyl group in a side chain.
-Imidazole derivatives have been described. Therefore, an imidazole derivative having both an unsaturated bond and a hydroxyl group in the side chain is expected to have a substance excellent as an antibacterial agent.

[Object of the Invention] The present invention has been made in view of the above situation, and has a novel 2- [1] having both an unsaturated bond and a hydroxyl group in a side chain and having various other substituents. -(2-hydroxyethyl) ethenyl] -1H-imidazole derivative and a method for producing the same.

[Constitution of the Invention] The present invention relates to a compound represented by the general formula [I]: (Wherein, R ¹ represents a hydrogen atom, a lower alkyl group or an aryl group, R ² represents a lower alkyl group or an aryl group which may have a substituent, and R ¹ and R ² are An alkylene group may be formed, R ³ represents a lower alkyl group, and R ⁴ and R ⁵ each independently represent a hydrogen atom or a lower alkyl group.) 2- [1- (2- Hydroxyethyl) ethenyl] -1H-imidazole derivatives.

Further, the present invention provides a compound represented by the general formula [II]: (Wherein R ¹ , R ³ , R ⁴ , and R ⁵ are the same as described above).
(1-methylethenyl) -1H-imidazole derivatives,
In the presence of a compound selected from hexaalkylphosphoric triamide or tetraalkylethylenediamine, trialkylaluminum and organolithium, a compound of the general formula [III] (Wherein, R ⁶ and R ⁷ each independently represent a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent An aralkyl group, a saturated or unsaturated heterocyclic ring which may have a substituent, and R ⁶ and R ⁷ may be linked to each other to form an alkylene group.) General formula [IV] characterized by reacting (Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are the same as described above). Production of a 2- [1- (2-hydroxyethyl) ethenyl] -1H-imidazole derivative represented by the following formula: It is an invention of a method.

 Hereinafter, the present invention will be described in detail.

As R ^{1 in the} general formulas [I], [II] and [IV], besides a hydrogen atom, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group
Lower alkyl groups such as ert-butyl group and the like, for example, aryl groups such as phenyl group, tolyl group, xylyl group and naphthyl group are mentioned. As R ² in the general formula [I], for example, methyl group, ethyl group , n-propyl group, isopropyl group, n
Lower alkyl groups such as -butyl group, isobutyl group and tert-butyl group, for example, phenyl group, chlorophenyl group, 3,4
A substituted or unsubstituted aryl group such as a methylenedioxyphenyl group, a tolyl group, a xylyl group, a naphthyl group, a methylnaphthyl group; and the alkylene group formed by linking R ¹ and R ² to each other. , Trimethylene group,
Examples include a tetramethylene group and a pentamethylene group.
As R ^{3 in the} general formulas [I], [II] and [IV],
Methyl group, ethyl group, n-propyl group, isopropyl group, n
And lower alkyl groups such as -butyl group, isobutyl group and tert-butyl group, and are represented by the general formulas [I], [II] and [IV].
As R ⁴ and R ^{5 in} the above, besides a hydrogen atom, for example, lower alkyl groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group and the like can be mentioned. In general formulas [III] and [IV]
As R ⁶ and R ⁷ , in addition to a hydrogen atom, for example, a methyl group,
Chloromethyl group, ethyl group, dimethylaminoethyl group, n
A substituted or unsubstituted saturated alkyl group such as -propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-octyl group, for example, phenyl group, chlorophenyl group, 3,4-methylenedioxy Phenyl group, tolyl group,
Substituted or unsubstituted aryl groups such as xylyl group, naphthyl group and methylnaphthyl group, for example, substituted or unsubstituted aralkyl groups such as benzyl group, chlorobenzyl group, methoxybenzyl group, phenethyl group and methylphenethyl group, for example, Methylpyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, thiazolidinyl, tetrahydropyranyl, 1.4-dimethyl-2-piperazinyl, 1-
Substituted or unsubstituted saturated heterocycles such as ethyl-3-morpholinyl group, for example, 1-methylpyrrolyl group, furyl group, thienyl group, 1-methylimidazolyl group, isoxazolyl group, thiazolyl group, pyridyl group, pyrimidinyl group,
Examples of the substituted or unsubstituted unsaturated hetero environment such as a pyranyl group, a tetrahydroquinolyl group, a quinolyl group, and a phenoxathiynyl group include an alkylene group formed by connecting R ⁶ and R ⁷ to each other. , A trimethylene group, a tetramethylene group, a pentamethylene group and the like.

2- [1- (2) represented by the general formula [IV] according to the present invention.
-Hydroxyethyl) ethenyl] -1H-imidazole derivative is produced, for example, as follows.

That is, a 2- (1-methylethenyl) -1H-imidazole derivative represented by the general formula [II] is dissolved in an ether solvent, and the mixture is cooled in an inert gas stream under cooling with a hexaalkylphosphoric triamide or tetraalkylethylenediamine; And a trialkylaluminum (reaction accelerator), and further, under the same cooling, if necessary, an organic alkali metal in the presence of an organic alkali metal color indicator such as 2,2'-dipyridyl, and then adding a compound represented by the general formula [III And the mixture is stirred at a predetermined temperature for a predetermined time. After the reaction, for example, water in which an oxidized salt such as ammonium chloride, ammonium sulfate or the like is dissolved is added to the reaction solution to decompose and neutralize the organic lithium and the like, and the mixture is neutralized. The extract is dried and concentrated, and then subjected to ordinary isolation procedures such as distillation, column chromatography, etc., to obtain the desired product. It is optional to further purify this by distillation, column chromatography or the like.

As the 2- (1-methylethenyl) -1H-imidazole derivative represented by the general formula [II] used in the production method of the present invention, any of the substituents described above as examples of R ¹ , R ^{3 to} R ⁵ can be used. Combinations can be mentioned, and specifically, 1-methyl-2- (1-methylethenyl) -1H-imidazole, 1,4,5-trimethyl-2- (1-methylethenyl) -1H-imidazole , 1-Propyl-2- (1-methyl-1-butenyl) -1H-imidazole, 1-butyl-
4-ethyl-5-methyl-2- (1-methyl-1-propenyl) -1H-imidazole and the like.

Examples of the ether solvent used in the production method of the present invention include, for example, dimethyl ether, diethyl ether,
In addition to dialkyl ethers such as diisopropyl ether, cyclic ethers such as tetrahydrofuran (THF),
Examples include glymes such as ethylene glycol diethyl ether and diethylene glycol dimethyl ether, and THF is particularly preferable. The amount of the ether-based solvent to be used is not particularly limited as long as the 2- (1-methylethenyl) -1H-imidazole derivative is uniformly or sequentially dissolved as the reaction proceeds during the reaction. A volume of 5 to 30 times the weight of the 2- (1-methylethenyl) -1H-imidazole derivative is used.

It is a reaction accelerator used in the production method of the present invention. Examples of the alkyl groups of hexaalkylphosphoric triamide, tetraalkylethylenediamine and trialkylaluminum include lower alkyl groups such as methyl group, ethyl group, isopropyl group, n-butyl group, isobutyl group and tert-butyl group. Is mentioned. Specific examples of the hexaalkylphosphoric triamide include, for example, hexamethylphosphoric triamide, hexaethylphosphoric triamide, triethyltrimethylphosphoric triamide, and the like, with hexamethylphosphoric triamide being particularly preferred. Specific examples of the tetraalkylethylenediamine include, for example, tetramethylethylenediamine, tetraethylethylenediamine, tetraisopropylethylenediamine, and the like, with tetramethylethylenediamine being particularly preferred. Further, specific examples of trialkylaluminum include, for example, trimethylaluminum, triethylaluminum, triisopropylaluminum, etc., and triethylaluminum is particularly preferred.

Examples of the organic alkali metal used in the production method of the present invention include alkyl lithium, lithium dialkyl amide, and the like. Examples of these alkyl groups include
For example, lower alkyl groups such as methyl group, ethyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like can be mentioned. Specific examples of the alkyllithium include, for example, methyllithium, n-propyllithium, n-butyllithium, sec-butyllithium and the like, with n-butyllithium being particularly preferred. These alkyl lithiums are usually used as an n-hexane solution. In particular, in the case of n-butyl lithium, usually 1.6 M
Used as a solution. Further, specific examples of the lithium dialkylamide include, for example, lithium dimethylamide, lithium diethylamide, lithium diisopropylamide, and the like. In particular, lithium diisopropylamide is preferable.
Used in M cyclohexane solution. The temperature at the time of adding these reaction accelerators and the like does not greatly affect the reaction as long as it is −50 ° C. or lower.
Temperatures in the range 100 to -50C are preferred. Examples of the inert gas introduced through the reaction include gases such as nitrogen, helium, and argon.

Examples of the carbonyl compound used in the production method of the present invention include those obtained by arbitrarily combining the substituents described above as examples of R ⁶ and R ^7. Specifically, for example, acetaldehyde, octanal, Aldehydes such as benzaldehyde, 3,4-methylenedioxybenzaldehyde, phenylacetaldehyde, and furfural, for example, acetone, cyclohexanone, acetophenone,
Ketones such as benzophenone, 4,4'-dichlorobenzophenone, bis (3,4-methylenedioxy) benzophenone, ethylbenzylketone, and methylfurylketone.

2- (1-methylethenyl) in the production method of the present invention
The addition reaction of the -1H-imidazole derivative to the carbonyl compound may proceed at room temperature in some cases, but is preferably performed in the range of -100 to -50 ° C in order to further enhance the selectivity.
The reaction time varies slightly depending on the compound and other reaction conditions, but is usually about several minutes to several hours.

In addition, 2- (1) used as a raw material in the production method of the present invention.
The (-methylethenyl) -1H-imidazole derivative can be produced by the method disclosed in Japanese Patent Application Laid-Open Nos. 58-210067 and 59-78167, and more preferably by the present inventors. The following production method has been newly found by the Company.

That is, the 2-position unsubstituted 1H-imidazole derivative is anionized with an organic alkyl metal such as n-butyllithium in an ether-based solvent such as THF at a low temperature, and the anion is added to acetone and acetone at a low temperature in the same solvent. Addition to methyl ketones such as methyl benzyl ketone to give 1- (1H-imidazole-2-
Yl) -1-methylethanol derivative is produced and heated with a carboxylic anhydride such as acetic anhydride to cause a dehydration reaction. The obtained 2- (1-methylethenyl) -1H-imidazole derivative is Purification may be performed as necessary.

Examples are described below, but the present invention is not limited to these examples. In addition, 2- [1- (2-hydroxyethyl) ethenyl] -1H- described in Examples.
The measurement results and yields of the melting point, boiling point, IR and NMR of the imidazole derivative are summarized in Table 1.

[Examples] Example 1. (1) 1-Methyl-1- (1-methyl-1H-imidazol-2-yl) ethanol / 1/4 hydrate 1-methyl- (1-methyl-1-H-imidazol-2-yl) ethanol 8.21 g (100 mmol) of 1H-imidazole and 5 mg of 2,2'-dipyridyl
Was dissolved and cooled to -78 ° C. 1.6M at the same temperature
After confirming that a small amount of n-butyllithium n-hexane solution was dropped and the color of the solution turned red, 64 ml of the same solution (100 mm
l) was added dropwise and stirred for 15 minutes. Then, at the same temperature, 6.10 g (105 mmol) of acetone was added dropwise, and the mixture was stirred for 5 minutes.
After addition of, the solvent was distilled off under reduced pressure at 30-40 ° C. Water in the residue
A water-insoluble solid precipitated by adding 50 ml was separated by filtration, washed with water, and recrystallized from ethyl acetate to give 1-methyl-1- (1
-Methyl-1H-imidazol-2-yl) ethanol
13.50 g of 1/4 hydrate was obtained. 96% yield.

Mp: 130-131 ° C. Elemental analysis _{(C 7 H 12 N 2 O} · 1 / 4H 2 O) Calculated (%) 58.11 (C) 8.70 (H) 19.36 (N) Found (%) 58.18 (C) 8.38 (H) 18.95 (N) IR (KBr): 3100cm -1 (OH) 1 H-NMR (CDCl 3): δppm 1.65 (s, 6H, C H 3 × 2), 3.
03 (s, 1H, O H ), 3.83 (s, 3H, NC H 3), 6.70,6.73 (d
each, 1H each, N-C H = C H -N, J = 1Hz) (2) 1- methyl-2- (1-methylethenyl)-1H-
2.80 g (20 mmol) of 1-methyl-1- (1-methyl-1H-imidazol-2-yl) ethanol / 1/4 hydrate was dissolved in a mixed solvent of 10 ml of imidazole acetic acid and 2 ml of acetic anhydride.
Heated to reflux at ~ 140 ° C for 1 hour. After cooling, add 5 ml of water,
After concentration under reduced pressure to remove acetic acid, the residue was made alkaline by adding an aqueous solution of potassium carbonate to precipitate an oily substance.
This was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure in the presence of a trace amount of 2-tert-butylhydroquinone (polymerization inhibitor) to give 1-methyl-2- (1
-Methylitenyl) -1H-imidazole 2.10 g were obtained as an oil. 86% yield.

Boiling point: 85 ° C./3 mmHg IR (KBr): 1635 cm ^-1 (C = C) ¹ H-NMR (CDCl ₃ ): δ ppm 1.13 to 2.33 (d, 3H, CC H ₃ , J =
1Hz), 3.73 (s, 3H , NC H 3), 5.20,5.43quar each, 1H
_{each, = C H 2, J} = 1Hz each), 6.83,7.01 (d each, 1H e
ach, N-C H = C H -N, J = 1Hz) Example 1.1 - methyl-2- [1- (hydroxymethyl cyclohexylmethyl) ethenyl]-1H-synthetic nitrogen stream imidazole in dry THF 20 ml 1 -Methyl-2-
1.22 g of (1-methylethenyl) -1H-imidazole (10 m
mol) was dissolved and cooled to -78 ° C. 1.74 ml (10 mmol) of hexamethylphosphoric triamide at the same temperature
And 15% triethylaluminum n-hexane solution 0.55
After dropwise addition of 2,2'-dipyridyl at the same temperature, 6.4 ml (10 mmol) of a 1.6 M n-butyllithium n-hexane solution was added dropwise, and the mixture was allowed to stand for 10 minutes. Stirred. Then, at the same temperature cyclohexanone 1.05ml
(10 mmol) was added dropwise, and the mixture was stirred at −50 ° C. for 15 minutes. The reaction was stopped by adding 5 g of a saturated aqueous ammonium chloride solution, and the desired product was extracted with ethyl acetate.

After the obtained ethyl acetate solution was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [filler: Wakogel C-200 (trade name of Wako Pure Chemical Industries, Ltd.)]. The desired product (compound 1) 1.
04g was obtained. Yield 47%.

Examples 2 to 5. The same procedure was followed as in Example 1 except that the cyclohexanone used in Example 1 was replaced with acetone, acetophenone, benzophenone and 3,4-methylenedioxybenzaldehyde, respectively. [1- (2-hydroxyethyl) ethenyl] -1H-imidazole derivative (compounds 3 to
5) was obtained.

[Effects of the Invention] The present invention enables industrial production of 2- [1- (2-hydroxyethyl) ethenyl] -1H-imidazole derivatives having various substituents and is industrially and pharmaceutically useful. This is a remarkable effect in that various novel 2- [1- (2-hydroxyethyl) ethenyl] -1H-imidazole derivatives are provided.

Claims (2)

(57) [Claims] 1. A compound of the general formula [I] (Wherein, R ¹ represents a hydrogen atom, a lower alkyl group or an aryl group, R ² represents a lower alkyl group or an aryl group which may have a substituent, and R ¹ and R ² are An alkylene group may be formed, R ³ represents a lower alkyl group, and R ⁴ and R ⁵ each independently represent a hydrogen atom or a lower alkyl group.) 2- [1- (2- [Hydroxyethyl) ethenyl] -1H-imidazole derivative. 2. A compound of the general formula [II] (Wherein R ¹ , R ³ , R ⁴ , and R ⁵ are the same as described above).
(1-methylethenyl) -1H-imidazole derivatives,
In the presence of a compound selected from hexaalkylphosphoric triamide or tetraalkylethylenediamine, trialkylaluminum and organolithium, a compound of the general formula [III] (Wherein, R ⁶ and R ⁷ each independently represent a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent An aralkyl group, a saturated or unsaturated heterocyclic ring which may have a substituent, and R ⁶ and R ⁷ may be linked to each other to form an alkylene group.) General formula [IV] characterized by reacting (Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are the same as described above). Production of a 2- [1- (2-hydroxyethyl) ethenyl] -1H-imidazole derivative represented by the following formula: Method.