JPS6151587B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 1-triphenylmethylimidazoles, which comprises reacting a trivalent organic phosphorus compound having one or two 1-imidazolyl groups with triphenylmethanols. As an organic phosphorus compound having 1 or 2 1-imidazolyl groups, for example, the general formula () [Wherein, A represents a substituted or unsubstituted 1-imidazolyl group, B and C are the same or different lower alkyl group, aryl group, lower alkoxy group,
Aryloxy group, lower alkylamino group, arylamino group, lower alkylmercapto group, arylmercapto group or

Indicates a substituent represented by the formula. However, R ₁ and R ₂ are the same or different lower alkyl groups or cycloalkyl groups, or R ₃ and R ₄ are lower alkylene chains bonded to each other or alkylene chains via nitrogen, oxygen, or sulfur atoms. Together with the adjacent nitrogen atom, it represents a cyclic amino group. When B is a substituent other than the above, it represents the same 1-imidazolyl group as A. ] Examples include organic phosphorus compounds having one or two 1-imidazolyl groups represented by the following. In the above formula, lower refers to 1 to 8 carbon atoms. The 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, such as para-nitrophenyl, orthochlorophenyl, para-methoxyphenyl, meta- Examples include, but are not limited to, methylphenyl and biphenyl groups. Examples of the 1-triphenylmethylimidazoles obtained by the present invention include 1-triphenylmethylimidazoles obtained by reacting the organic phosphorus compound of the general formula () with the triphenylmethanols described above. 1-Triphenylmethylimidazole obtained by the present invention is a known compound and is already known to exhibit antibacterial activity [Chem.Ber., 92
Volume, 92 pages (1959): Chem.Ber., 93 volumes, 570 pages (1960): Chem.Ber., 93 volumes, 576 pages (1960)
): Special Publication No. 18752]. 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. 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, 1-triphenylimidazoles can be produced by heating triphenylmethanols and imidazoles at a temperature of 140 to 230°C (Japanese Patent Publication No. 47-20015). This method has an industrial advantage in that it does not use triphenylmethyl halides, but on the other hand, it uses inert triphenylmethanols, so it does not require high temperatures, which is an industrial disadvantage. However, it has drawbacks such as poor yield and low yield. As described above, triphenylmethanols are generally more inert than triphenylmethyl halides, and therefore have significantly less reactivity. Therefore, if the reaction is to be carried out at an industrially advantageous temperature, it is necessary to convert imidazoles into active derivatives. Therefore, when using triphenylmethanol as a raw material, the reaction is limited and only three methods are currently known, and most of the many known methods for producing 1-triphenylmethylimidazole are Triphenylmethyl halides are used as starting materials. Currently known methods using active derivatives of imidazoles include thionyl imidazolide [Ann., Vol. 694, p. 86 (1966)] or carbonyl diimidazole [Arzneim Forsch, 22 No. 8,
1260 (1966)] and triphenylmethanols (Japanese Patent Application Laid-Open No. 1522-1983). The present inventors are conducting research on the synthesis of organic phosphorus compounds.
- Trivalent organic phosphorus compounds having 1 or 2 imidazolyl groups, such as compounds represented by the general formula (), react with triphenylmethanols to form 1-
It was discovered for the first time that triphenylmethylimidazoles were formed. The characteristics of the method of the present invention include not only the industrial advantages of using triphenylmethanol as a raw material as described above, but also the fact that the reaction proceeds satisfactorily without requiring industrially disadvantageous high temperatures. It will be done. To explain the present invention in more detail, for example, a trivalent organic phosphorus compound having one or two 1-imidazolyl groups represented by the general formula () may be a trivalent organic phosphorus compound represented by the general formula () or the general formula (). [In the formula, X represents a halogen atom, B and C
is the same as above. ] It is produced by the reaction of the halogenated phosphorus compound represented by the following with a trialkylsilyl imidazole substituted or unsubstituted at the 2, 4 or 5 position of the imidazole ring. or a compound of general formula () or general formula () and 2 of the imidazole ring,
It can be produced by reacting imidazoles substituted or unsubstituted at the 4- or 5-position in the presence of an acid binding agent. 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, nitrogen-containing compounds such as dimethylformamide, pyridine, and acetonitrile, and sulfur-containing compounds such as dimethyl sulfoxide. etc., but is not particularly limited thereto. Furthermore, since this reaction is an exothermic reaction, it is desirable to cool it. In the reaction of a trivalent organic phosphorus compound having 1 or 2 imidazolyl groups with triphenylmethanol, for example, the compound of the general formula () obtained by the above method does not require particular isolation and purification.
Even if triphenylmethanol is directly added to the reaction mixture obtained by the above method and reacted, the target product, 1-triphenylmethylimidazole, can be obtained. In this reaction, any solvent can be used as long as it does not interfere with the reaction, and usually acetonitrile, chloroform, dimethylformamide, methylene chloride, etc. can be used. Although the reaction can proceed at room temperature, since the reaction rate is slow, it is usually preferable to carry out the reaction at the boiling point of the solvent used for the purpose of promoting the reaction. For example, when the organic phosphorus compound of the general formula () has one imidazolyl group, it is usually used in an amount equal to or more than the same mole relative to triphenylmethanol;
If you have one, use 1/2 times the mole or more. Generally, it is convenient to use an excess of an organic phosphorus compound for the purpose of accelerating the reaction, but it is usually preferred from an industrial standpoint to use an amount in the range of 1/2 to 10 times the mole. Next, details will be explained using examples. Example 1 1.40 g of trimethylsilylimidazole in a chloroform solution of 1.57 g of diethylchlorophosphite
was added under ice-cooling and allowed to react at 0 to 15°C for 1 hour.
When the solvents are distilled off under reduced pressure, 1.9 g of crude crystals of diethyl (1-imidazolyl) phosphite are left as a residue.
I got it. Melting point 85-95℃ NMR (CCl ₄ ): δ7.60 (1H, broad s., imidazole C ₂ -H) 7.00 (2H, broad s., imidazole C ₄ ,
C ₅ -H) 3.90 (4H, quintet, -O-CH ₂ -CH ₃ ) 1.20 (6H, t., -O-CH ₂ -CH ₃ ) Dissolve this substance again in chloroform and add 2.08 g of triphenylmethanol. and react at 0 to 20°C for 3 hours. The reaction solution is washed with water, then washed with a 5% aqueous potassium carbonate solution, and further washed twice with water. The resulting chloroform layer was dried and the solvent was distilled off to obtain 1.7 g of crude crystals, which were further recrystallized from acetonitrile to give 1.37 g of 1-triphenylmethylimidazole (yield 55.2%) with a melting point of 217-220°C. ) was obtained. Elemental analysis values Calculated values C = 85.13% H = 5.85% N = 9.03% (as C ₂₂ H ₁₈ N ₂ ) Actual values C = 84.90% H = 6.04% N = 9.21% Example 2 2.80 g of trimethylsilylimidazole in chloroform (20mM) and 1.79g (10mM) of dichlorophenylphosphine were reacted at 0 to 20℃ for 1 hour, and the solvent was distilled off under reduced pressure to obtain phenyldi(1-imidazolyl)phosphine as a residual oil. . NMR (CDCl ₃ ): δ7.93 (2H, broad s., imidazole C ₂ -H) 7.4-7.8 (5H, m., benzene H) 7.18 (4H, broad s., imidazole C ₄ ,
C ₅ -H) This substance was dissolved in chloroform again, 2.60 g (10 mM) of triphenylmethanol was added, and the mixture was heated under reflux for 4 hours, and then post-treated in the same manner as in Example 1 to give 2.82 g of crude crystals. obtained, and further recrystallized from acetonitrile to obtain 1-
Triphenylmethylimidazole 2.09g (yield 75
%) was obtained. Example 3 6.1 g (0.03 M) of bis(trimethylsilyl)acetamide and 1.36 g of imidazole in chloroform
(0.02M) and 0.85g (0.01M) of piperidine were added and dissolved, and 1.37g (0.01M) of phosphorus trichloride was added to the solution.
Add dropwise at 10℃. After completion of the dropwise addition, the reaction was further stirred at the same temperature and the solvent was distilled off under reduced pressure to obtain di(1-imidazolyl)-1-piperidinophosphine as a residual oil. NMR (CDCl ₃ ): δ7.55 (2H, broad s., imidazole C ₂ -H) 6.90 (4H, broad s., imidazole C ₄ ,
C ₅ - H) 2.57-3.33 (4H, m., piperidine C ₂ , C ₆ -
H) 1.0-1.73 (6H, m., piperidine _C3 , _C4 , _C5
-H) Dissolve this substance in chloroform again, add 2.6 g (0.01M) of triphenylmethanol, heat under reflux for 5 hours, and then work up in the same manner as in Example 1 to obtain 3.8 g of crude crystals. Furthermore, 1-
Triphenylmethylimidazole 1.3g (yield 42
%) was obtained. Example 4 1.36 g (0.02 mol) of imidazole and 3.03 g (0.03 mol) of triethylamine were added to 30 ml of chloroform.
Add 1.37 g (0.01 g) of phosphorus trichloride to a solution dissolved in
0.85 g (0.01 mol) of piperidine is added dropwise. After stirring at 0 to 10°C for about 1 hour, 2.6 g of triphenylmethanol is added to the resulting di(1-imidazolyl)-1-piperidinophosphine.
(0.01 mol) was added to this solution at reflux temperature (67-68
℃) for 2 hours. After the reaction is complete, cool to room temperature and add 30ml of water to 10% potassium carbonate aqueous solution.
After sequentially washing with 20 ml of water, wash three times with 50 ml of water. After drying the chloroform layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3.93 g of pale yellow crystals.
Obtain mp.204-208℃. Add 50ml of isopropyl ether to this and heat soak to obtain 3.03g of white crystals.
(97.6%) mp.210~213℃ acetonitrile 80ml
2.6g (83.8%) of colorless needle crystals
Obtain 1-triphenylmethylimidazole with mp.216-217°C. The identity of this product was confirmed by NMR and IR with a standard product synthesized by a known method. Example 5 Using the same method as in Example 4, add 30 ml of chloroform,
Imidazole 1.36g, triethylamine 3.03g,
Using 1.37g of phosphorus trichloride, 0.85g of piperidine, and 2.94g of O-chlorophenyldiphenylmethanol,
The obtained crude crystals were recrystallized from acetonitrile to give 1-
2.55 g (yield 74%) of crystals of [O-chlorophenylbisphenylmethyl]imidazole were obtained. melting point
140-141℃ Elemental analysis value Calculated value C=76.63%, H=4.97% N ₌ 8.12% (as _C22H17N2Cl ) _Actual value C=76.40% H=4.71% N=7.97% Example 6 Implementation 30 ml of chloroform in the same manner as in Example 4;
Imidazole 1.36g, triethylamine 3.03g,
Using 1.37 g of phosphorus trichloride, 0.73 g of n-butylamine, and 2.6 g of triphenylmethanol, the obtained crude crystals were recrystallized from acetonitrile to obtain 2.5 g of crystals of 1-triphenylmethylimidazole (yield: 80.6).
%) was obtained. Melting point: 214-216°C Example 7 Using the same method as in Example 4, add 30 ml of chloroform,
Imidazole 1.36g, triethylamine 3.03g,
The obtained crude crystals were recrystallized from acetonitrile using 1.37 g of phosphorus trichloride, 0.93 g of aniline, and 2.6 g of triphenylmethanol to obtain 2.1 g of crystals of 1-triphenylmethylimidazole (yield 67.7%). Melting point: 217-218°C Example 8 Using the same method as in Example 4, add 30 ml of chloroform,
Imidazole 1.36g, triethylamine 3.03g,
Using 1.37 g of phosphorus trichloride, 0.6 g of ethylenediamine, and 2.6 g of triphenylmethanol, the obtained crude crystals were recrystallized from acetonitrile to obtain 2.48 g of crystals of 1-triphenylmethylimidazole (80% yield).
I got it. Melting point: 223-224°C Example 9 Using the same method as in Example 4, add 30 ml of chloroform,
Imidazole 1.36g, triethylamine 3.03g,
Phosphorus trichloride 1.37g, ethylenediamine 0.6g, O-
The obtained crude crystals were recrystallized from acetonitrile using 2.94 g of chlorophenyldiphenylmethanol to obtain 1.5 g of crystals of 1-[O-chlorophenylbisphenylmethyl]imidazole (yield: 43.5%). Melting point: 137-142°C Example 10 Using the same method as in Example 4, add 30 ml of chloroform,
Imidazole 0.68g, triethylamine 3.03g,
The obtained crude crystals were recrystallized from acetonitrile using 1.37 g of phosphorus trichloride, 1.7 g of piperidine, and 2.6 g of triphenylmethanol to obtain 1.8 g of crystals of 1-triphenylmethylimidazole (yield 58%). Melting point: 219-220°C Example 11 Using the same method as in Example 4, add 30 ml of chloroform,
Imidazole 0.68g, triethylamine 3.03g,
Using 1.37 g of phosphorus trichloride, 1.46 g of n-butylamine, and 2.6 g of triphenylmethanol, the obtained crude crystals were recrystallized from acetonitrile to obtain 1.5 g of crystals of 1-triphenylmethylimidazole (yield: 48.3
%) was obtained. Melting point: 220-221°C Example 12 30 ml of chloroform in the same manner as in Example 4,
Imidazole 0.68g, triethylamine 3.03g,
Using 1.37 g of phosphorus trichloride, 0.6 g of ethylenediamine, and 2.6 g of triphenylmethanol, the obtained crude crystals were recrystallized from acetonitrile to obtain 1.1 g of crystals of 1-triphenylmethylimidazole (yield: 35.4
%) was obtained. Melting point: 217-218°C Example 13 Using the same method as in Example 4, add 30 ml of chloroform,
Imidazole 1.36g, triethylamine 3.03g,
The obtained crude crystals were recrystallized from acetonitrile using 1.37 g of phosphorus trichloride, 0.32 g of methanol, and 2.6 g of triphenylmethanol to obtain 2.29 g of crystals of 1-triphenylmethylimidazole (yield: 73.9%). Melting point: 217-219°C Example 14 Using the same method as in Example 4, add 30 ml of chloroform,
Imidazole 0.68g, triethylamine 3.03g,
The obtained crude crystals were recrystallized from acetonitrile using 1.37 g of phosphorus trichloride, 0.64 g of methanol, and 2.6 g of triphenylmethanol to obtain 2.08 g of crystals having a melting point of 129 to 200°C. This substance was determined by NMR,
It is a mixture of triphenylmethanol and the desired 1-triphenylmethylimidazole in a ratio of about 2:1. Example 15 Using the same method as in Example 1, add 30 ml of chloroform,
1.40 g of trimethylsilylimidazole, 1.27 g of 2-chloro-1,3,2-dioxaphosphoran,
Using 1.73 g of triphenylmethanol, the obtained crude crystals were recrystallized from acetonitrile to obtain 0.41 g of 1-triphenylmethylimidazole crystals (yield: 20
%) was obtained. Melting point 216-219℃

Claims (1)

[Claims] 1 3 having 1 or 2 1-imidazolyl groups
1. A method for producing 1-triphenylmethylimidazole, which comprises reacting a divalent organic phosphorus compound with triphenylmethanol. 2 1-triphenylmethylimidazole is 1
-Triphenylmethylimidazole.The manufacturing method according to claim 1. 3 1-triphenylmethylimidazole is 1
-[O-chlorophenylbisphenylmethyl]imidazole, the manufacturing method according to claim 1.