JP5044785B2 - Urea compound and thiourea compound and organogel using the same - Google Patents

Description

  The present invention relates to a urea compound and a thiourea compound and an organogel using the same.

  Gels are widely used in the field of food and environmental protection, such as adding to paints and adjusting fluidity in the fields of paints and resins, etc., or gelling waste oil to form solids to prevent water contamination. ing. A gel is a structure in which a fluid such as water or an organic solvent is contained in a three-dimensional network structure formed of a chemical substance. An organogel is used when the fluid is an organic solvent, and a hydrogel is used when the fluid is water. .

  In recent years, it has been reported that a low molecular compound having a urea group is used as a gelling agent for an organic solvent (for example, Patent Document 1). As examples of such low-molecular gelling agents, Patent Document 1 discloses a compound represented by Formula (1), and Patent Document 2 discloses a compound represented by Formula (2).

（式（１）において、
Ｒ_１は炭素原子数が７〜２１の直鎖又は分岐鎖のアルキル基又はアルケニル基、
Ｒ_２は炭素原子数が１〜２２の直鎖若しくは分岐及び／又は環状を有するアルキル基若しくはアルケニル基、
Ｒ_３は炭素原子数が８〜２２の直鎖若しくは分岐及び／又は環状を有するアルキル基若しくはアルケニル基、
ｎは２〜４の整数を示す。）

(In Formula (1),
R ₁ is a linear or branched alkyl or alkenyl group having 7 to 21 carbon atoms,
R ₂ is a linear or branched and / or cyclic alkyl group or alkenyl group having 1 to 22 carbon atoms,
R ₃ is a linear or branched and / or cyclic alkyl group or alkenyl group having 8 to 22 carbon atoms,
n shows the integer of 2-4. )

（式（２）において、
Ｒ_１、Ｒ_２およびＲ_３は、同一または異なって、アルキルを表す。）

(In Formula (2),
R ₁ , R ₂ and R ₃ are the same or different and each represents alkyl. )

（式（３）において、
Ｒは、C₁₂H₂₅または、以下の式（３ａ）で表される基である。） Non-Patent Document 1 discloses a compound represented by formula (3).

(In Formula (3),
R is C ₁₂ H ₂₅ or a group represented by the following formula (3a). )

Furthermore, Non-Patent Document 2 discloses a compound represented by the formula (4).

It is also known that when an external stimulus is applied to the gel, it is transferred to the sol. Materials that easily cause gel-sol transition are being studied for application to drug delivery systems as stimuli-responsive materials. The most common external stimulus is temperature. For example, Patent Document 3 discloses that an organogel capable of reversible transition to a gel-sol-gel (reversible sol-gel transition) by changing the temperature and the gel are formed. A low molecular weight gelling agent is disclosed. Furthermore, Patent Document 4 discloses an organogel capable of reversible sol-gel transition using UV light as an external stimulus and Patent Document 5 as an external stimulus and a low-molecular gelling agent that forms the organogel.
JP 2000-256303 A JP 2004-359543 A JP 2000-229992 A JP-A-5-247084 JP 2000-126585 A The Chemical Society of Japan, “Basics of Modern Interfacial Colloid Chemistry”, Second Edition, Maruzen Co., Ltd., May 2002, p. 117 Jan H.van Eschand Ben L. Feringa, AngewandteChemie International Edition, (Germany), 2000, vol.39, No.13, p.2263

The gel is based on the formation of a three-dimensional network structure by combining the compounds with each other to form a fiber structure. The root of the bond between the compounds is considered to be mainly a hydrogen bond due to a urea group or the like. As described above, the three-dimensional network structure includes a fluid such as an organic solvent to form a gel.
Any urea compound having conventional gelling properties has a long-chain alkyl group. Although details are not clear, it is believed that this long-chain alkyl group works as a rule of thumb for a low-molecular gelling agent to increase the gelling ability. However, no urea compound having a structure having no long-chain alkyl group and having a gelling ability has been reported. Therefore, a novel compound having an unprecedented chemical structure and excellent gelation ability such as an organic solvent has been desired.

Further, conventional organogels having reversible sol-gel transition properties are those having external stimuli of temperature, ultraviolet light, and pH, but organogels having reversible sol-gel transition properties by other external stimuli have been desired. In particular, the reversible sol-gel transferability of organogels with UV and pH as external stimuli is presumed to depend largely on the chemical structure of the gelling agent. Therefore, a compound with an unprecedented chemical structure is designed and used. An organogel having reversible sol-gel transition has been desired.
That is, an object of the present invention is to provide a compound having an unprecedented chemical structure and exhibiting excellent gelling properties, and an organogel capable of reversible sol-gel transition using the compound.

As a result of intensive studies, the inventor has found that a compound having a benzene ring as a mother nucleus and having a urea group or a thiourea group introduced at a position with good symmetry achieves the above object, and has completed the present invention. That is, the said subject is solved by the urea compound or thiourea compound of this invention shown below.
[1] A urea compound or a thiourea compound represented by the following formula (5).
[2] An organogel comprising the urea compound or thiourea compound according to [1] above and an organic solvent having a polar group.
[3] An organosol containing the urea compound or thiourea compound according to [1], an organic solvent having a polar group, and an anion.

Moreover, the said subject is solved by the manufacturing method of the organogel or organosol using the urea compound or thiourea compound of this invention shown below.
[4] A step of mixing the urea compound or thiourea compound according to [1] above and an organic solvent having a polar group,
Irradiating the mixture with ultrasonic waves,
The manufacturing method of the organogel containing.
[5] A method for producing an organosol, comprising: preparing the organogel according to [2]; and mixing an anion with the organogel.
[6] A method for producing an organogel comprising the step of preparing the organosol according to [3], and the step of mixing zinc bromide or boron trifluoride into the organosol.
[7]
A) Step of preparing the organogel as described in [2] B) Step of mixing anion with the organogel and transferring it to the organosol C) Mixing the gel with zinc bromide or boron trifluoride, and again into the organogel Step of transferring D) Further, B) or B) and C) step.

  The present invention can provide a compound having an unprecedented chemical structure and exhibiting excellent gelling properties, and an organogel capable of reversible sol-gel transition using the compound.

1. 1. Urea and thiourea compound of the present invention 1) Structure The urea and thiourea compound of the present invention is represented by the formula (5). Hereinafter, the urea and thiourea compounds of the present invention are referred to as “(thio) urea compounds”.

  In Formula (5), X is an oxygen atom or a sulfur atom. In view of easy availability of raw materials, oxygen atoms are preferred.

  In Formula (5), Y is an aryl group and may have a substituent. The aryl group refers to a residue obtained by removing one hydrogen atom from the nucleus of an aromatic hydrocarbon, and examples thereof include a phenyl group, a naphthyl group, a biphenyl group, and those having a substituent introduced therein. As will be described later, Y is preferably a phenyl group because it is excellent in the ability to gel an organic solvent having a polar group (gelation ability). Alternatively, it may be an alkylphenyl group. In that case, an alkylphenyl group in which an alkyl group having 1 to 3 carbon atoms is substituted at the ortho position or the meta position is preferable, and an m-toluyl group in which a methyl group is introduced at the meta position is particularly preferable.

  In the formula (5), Z is an arylene group. The arylene group means a residue obtained by removing two hydrogen atoms from the nucleus of an aromatic hydrocarbon, and examples thereof include a ferene group, a naphthylene group, a biphenylene group, and those having a substituent introduced therein. Z is preferably a phenylene group because of its excellent gelling ability. Especially, the structure (m-phenylene group or o-phenylene group) in which the nitrogen atom of the urea group is bonded to the ortho position or the meta position with respect to the site where the oxygen atom of the benzene ring is bonded. preferable. Among these, an m-phenylene group is more preferable.

  In the formula (5), R is a hydrogen atom or an alkyl group. The alkyl group is more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably an ethyl group, because of its excellent gelling ability.

2) Production method The (thio) urea compound of the present invention can be synthesized in three stages using a benzene derivative as a raw material. An example of the synthesis method is shown below.

第一工程：アルゴン雰囲気下、メタニトロフェノール（９．４ｇ：６７ｍｍｏｌ）、炭酸カリウム（９．３ｇ：６７ｍｍｏｌ）のアセトン懸濁液（１３０ｍｌ）を氷浴にて冷却し、上記（６）の化合物である１，３，５−トリス（ブロモメチル）−２，４，６−トリエチルベンゼン（９．９ｇ：２２ｍｍｏｌ）を加える。反応懸濁液を室温にまで昇温し、１７時間程度反応させる。次に反応液をロータリーエバポレーターにて濃縮したのち、クロロホルムを加え、ろ過し、不溶の炭酸カリウムを除去する。ろ液を濃縮した後、得られた残渣を塩化メチレン、ノルマルヘキサンの混合溶媒を用いて再沈殿する。続いて、当該結晶を濾過により得て、真空加熱乾燥することで、純粋なニトロ体（７）が白色固体として得られる。収量は１１．８ｇ（８６％）程度である。
ここでは例として１，３，５−トリス（ブロモメチル）−２，４，６−トリエチルベンゼンを示したが、臭素以外のハロゲン原子を有するものでもよい。また、メタニトロフェノールを例示したが、パラ体、オルト体でもよい。

First step: Under an argon atmosphere, an acetone suspension (130 ml) of metanitrophenol (9.4 g: 67 mmol) and potassium carbonate (9.3 g: 67 mmol) was cooled in an ice bath, and the compound of (6) above 1,3,5-tris (bromomethyl) -2,4,6-triethylbenzene (9.9 g: 22 mmol) is added. The reaction suspension is warmed to room temperature and allowed to react for about 17 hours. Next, after concentrating a reaction liquid with a rotary evaporator, chloroform is added and it filters and removes insoluble potassium carbonate. After concentrating the filtrate, the obtained residue is reprecipitated using a mixed solvent of methylene chloride and normal hexane. Subsequently, the crystals are obtained by filtration, and dried by heating under vacuum to obtain a pure nitro compound (7) as a white solid. The yield is about 11.8 g (86%).
Here, 1,3,5-tris (bromomethyl) -2,4,6-triethylbenzene is shown as an example, but it may have a halogen atom other than bromine. Moreover, although metanitrophenol was illustrated, a para body and an ortho body may be sufficient.

Second Step: Under argon atmosphere, a 1,4-dioxane solution (5 ml) of nitro compound (7) (500 mg: 0.8 mmol) and tin dichloride dihydrate (2.8 g: 12 mmol) at room temperature. Stir for 2 hours, warm to 50 ° C. and react for an additional 3 hours. Next, the reaction solution is ice-cooled, and water is added to stop the reaction. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution to neutralize the reaction solution, and then the insoluble solid is removed by Celite filtration, and the solid is washed with ethyl acetate. The filtrate is separated into an organic layer and an aqueous layer with a separatory funnel, and the target compound is extracted from the aqueous layer with ethyl acetate. The ethyl acetate used for extraction and the organic layer separated from the filtrate are mixed, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate is concentrated on a rotary evaporator. The obtained residue is purified by silica gel column chromatography (SiO ₂ , Hexane / EtOAc = 1/1) to obtain the amine body (8) as a white solid. The yield is about 365 mg (86%).

  Third step: Under an argon atmosphere, a solution of amine compound (8) (1.8 g: 3.4 mmol) in methylene chloride (25 ml) is cooled in an ice bath, and phenyl isocyanate (1.2 ml: 11 mmol) is added. The reaction suspension is warmed to room temperature and allowed to react for 2 days. Normal hexane is added to the reaction mixture, and the solid is collected by filtration. This solid is washed with a mixed solvent of acetone and normal hexane, and then dried under vacuum heating to obtain a pure urea compound (5) as a white solid. The yield is about 2.4 g (80%).

3) Applications, etc. Since the (thio) urea compound of the present invention has urea groups and thiourea groups, which are functional groups, it can be used for various applications such as pharmaceuticals, pharmaceutical intermediates, polymer raw materials, and polymer additives. However, among these, it is suitably used as a gelling agent for organic solvents having a polar group. That is, the compound of the present invention forms an organogel with an organic solvent having a polar group. Details of the organogel will be described later.

2. About the organogel of the present invention The organogel of the present invention (hereinafter simply referred to as “gel”) is mainly composed of a) the (thio) urea compound of the present invention and b) an organic solvent having a polar group.

1) Composition The organogel of the present invention includes a) the (thio) urea compound of the present invention, and b) an organic solvent having a polar group. Although the ratio will not be specifically limited if it is a ratio which can form a gel, It is preferable that a) a compound is 1-10 mass% with respect to the sum total of a) and b), and is 2-5 mass%. It is more preferable. It is because a gel can be formed efficiently.

  The organic solvent means a liquid used for dissolving a substance or a solid organic compound having a relatively low melting point. The organic solvent in the present invention needs to have a polar group in the molecule. This is because it is easily gelled by the (thio) urea compound of the present invention. A polar group is a group containing oxygen, nitrogen, sulfur, and halogen atoms. Examples of such organic solvents include ketone solvents such as acetone, alcohol solvents such as methanol, and diethyl phthalate. Ether solvents such as ester solvents and tetrahydrofuran are included. From the viewpoint of excellent workability when gelling, the organic solvent in the present invention is preferably a liquid at room temperature, but the (thio) urea compound of the present invention is also suitably used in a solvent that is solid at room temperature. .

Although the structure of the said gel is not specifically limited, For example, it may be the following structures.
First, a hydrogen atom and an X atom (oxygen or sulfur atom) in a (thio) urea compound molecule are hydrogen bonded to a hydrogen atom and an X atom of another (thio) urea compound molecule, thereby overlapping in a one-dimensional direction. Fibrous structures are formed, and these form a three-dimensional network structure. At that time, π electrons existing in the aromatic ring of Y in the (thio) urea compound interact with π electrons of Y of other (thio) urea compound molecules (π stacking), so that the (thio) urea compounds are It is thought that the bond (overlapping) is strengthened.
The organic solvent is present in the cavity of the three-dimensional network structure formed in this way, forming the gel.

  Further, the gel comprising a) and b) of the present invention is disintegrated into an organosol (hereinafter simply referred to as “sol”) when c) anions are mixed. The sol is a colloid having an organic solvent as a dispersion medium and a solid as dispersed particles. A colloid means a state in which a substance is not recognized at the optical microscope level but exists as a particle larger than an atom or a small molecule. The transition to the sol is presumed to be due to the fact that the hydrogen bonds overlapping the (thio) urea compounds are inhibited by c) and the three-dimensional network structure is destroyed.

  Here, an anion means an atom (group) or molecule having a negative charge. Examples of the anion include halide ion, acetate ion, boron tetrafluoride ion, phosphate ion, sulfate ion and the like. The anion is preferably used as a salt because it can be easily added to the gel. Examples of these salts include inorganic salts such as sodium salt, potassium salt and calcium salt, and organic salts such as tetrabutylammonium salt, tetraethylammonium salt and tetramethylammonium salt. Of these, organic salts are preferred because of their excellent solubility in gels, and tetrabutylammonium salts are preferred because of their easy transition to sols.

Further, when d) zinc bromide or boron trifluoride is mixed with the sol, a gel is formed again. This is considered because the anion of c) is trapped in d) and the hydrogen bond is regenerated. Zinc bromide is a compound (ZnBr ₂ ) formed by combining zinc atoms and bromine atoms in a ratio of 1: 2, and boron trifluoride is a compound formed by combining boron atoms and fluorine atoms in a ratio of 3: 1. (BF ₃ ). Boron trifluoride is preferably used as its diethyl ether complex (BF ₃ · OEt ₂ ) from the viewpoint of handleability. Hereinafter, the component d) may be referred to as “zinc bromide and the like”.

Therefore, the organogel of the present invention may further contain c) an anion and d) zinc bromide or boron trifluoride in the above a) and b). However, in order to be a gel, it is important that c) and d) have a specific ratio. That is, it is necessary to have an amount of d) capable of trapping c) presumed to inhibit the hydrogen bond. Since this ratio largely depends on the gel production method, it will be explained in the production method section.
There are also preferred combinations of c) and d). When zinc bromide is used as d), fluoride ion, chloride ion, bromide ion, iodide ion, acetate ion or phosphate ion is preferred. When boron trifluoride is used, fluoride ion, acetate Ions or phosphate ions are preferred. In addition, the zinc bromide and boron trifluoride of component d) may be used alone or in combination.

  In addition to the above-described components, the gel may contain other components as long as the properties of the gel are not impaired. Examples of such additives include amino acids that are useful when the gel is compatible with biomaterials, and neutral substances such as triphenylphosphine that are considered effective when used as industrial materials.

2) Production method The gel is obtained by mixing a) the compound of the present invention and b) an organic solvent having a polar group. The mixing method is not particularly limited, but it is preferable to add external energy by ultrasonic irradiation or the like after b) adding the compound a) to the organic solvent and stirring with a glass rod or the like. Although the time for irradiating the ultrasonic wave depends on the amount of the mixed system of a) and b), it is preferably irradiated for 5 to 10 minutes when the whole system is 1 to 10 ml.
The gel obtained by this production method is referred to as “virgin gel”.

Moreover, when the gel of this invention contains c) anion, d) zinc bromide, etc. in a) and b), it can be obtained by the following method.
(I) Method of mixing components a) to d) Mixing is preferably performed by irradiating ultrasonic waves under the conditions as described above.

(Ii) A method of preparing an organosol (hereinafter simply referred to as “sol”) containing components a) to c) and mixing d) with this. Mixing is preferably performed by irradiating ultrasonic waves under the conditions as described above. . In this case, the mixing amount of d) is preferably 0.8 molar equivalents or more, more preferably 1-2 molar equivalents, relative to c). The molar equivalent is a value divided by the number of moles of the compound based on the number of moles of the corresponding component.
The step of preparing the sol is not particularly limited, but may be obtained by mixing a) to c).

(Iii) Method of Regenerating Virgin Gel It may be obtained by mixing virgin gel with c) to form a sol, and further mixing d) to regenerate the gel. The regenerated gel in this case is referred to as “one-time regenerated gel”. The amount of c) mixed at this time is preferably 0.8 to 5 molar equivalents, more preferably 1.1 to 3 molar equivalents, relative to the (thio) urea compound in the virgin gel.
Further, the amount of d) to be mixed is preferably 0.8 molar equivalents or more, more preferably 1 to 2 molar equivalents relative to c) as already described.

Further, c) and d) may be mixed in the same manner as the once regenerated gel to obtain a regenerated gel multiple times. The number of regenerations is not particularly limited, but is preferably 1 to 4 times because of the solubility of each component in the gel. In this case, the preferred ratio of each component of the gel is as follows.
For a once regenerated gel,
a) is 1 to 10% by mass, more preferably 2 to 5% by mass, based on the sum of a) and b)
c) is 0.8 to 5 molar equivalents relative to a), more preferably 1.1 to 3 molar equivalents d) is 0.8 molar equivalents or more relative to c), more preferably 1 to 2 equivalents.
In the case of 4 times regenerated gel,
Since c) is 4 times the amount of the regenerated gel, 3.2 to 20 molar equivalents, more preferably 4.4 to 12 molar equivalents of a) d) is 4 times the amount of the once regenerated gel. Therefore, it is 3.2 molar equivalents or more, more preferably 4 to 8 molar equivalents relative to c).

From the above, the preferred ratio of each component of the gel containing a) to d) is
a): 1 to 10% by mass, more preferably 2 to 5% by mass, based on the sum of a) and b)
c): 0.8-20 molar equivalents relative to a), more preferably 1.1-12 molar equivalents d): 0.8 molar equivalents or more relative to c), more preferably 1-8 molar equivalents. Become.

3) Uses, etc. The gel obtained in the present invention is a strong and stable gel and is suitable for flow regulators such as paints and resins. Furthermore, since it can be regenerated, it can be applied to a drug delivery system or the like as a stimulus-responsive gel.

  The gel may be used as a xerogel. Xerogel refers to a structure in which gas (air) is contained in a three-dimensional network structure formed of a compound. It can be prepared by removing the organic solvent from the organogel. Examples of the method for removing the organic solvent include drying, drying under reduced pressure, freeze drying and the like.

3. About the organosol of the present invention The organosol (sol) of the present invention is mainly composed of a) the compound of the present invention, b) an organic solvent having a polar group, and c) an anion.

1) Composition The sol comprises a) a compound of the present invention, b) an organic solvent having a polar group, and c) an anion. The ratio is not particularly limited as long as it is a ratio capable of forming a sol, but a preferable ratio is shown below.
a): 1 to 10% by mass, more preferably 2 to 5% by mass, based on the sum of a) and b)
c): 0.8-5 molar equivalents relative to a), more preferably 1.1-3 molar equivalents

As already mentioned, the gel consisting of a) and b) becomes a sol by c) mixing anions, and d) again by mixing d) zinc bromide and the like. Therefore, the sol of the present invention may further contain d) zinc bromide or boron trifluoride in a), b) and c). However, in order to be a sol, it is important that c) and d) have a specific ratio. That is, even if a part of c), which is presumed to inhibit the hydrogen bond overlapping (thio) urea compounds, is trapped in d), an amount of c) that can exhibit the inhibitory activity remains. Need to be. Since this ratio largely depends on the manufacturing method of the sol, it will be described in the manufacturing method section.
There are also preferred combinations of c) and d), and the combinations are as described in 2.1). The component d), zinc bromide or boron trifluoride, may be used alone or in combination.

  In addition to a) to c), the sol may contain other components as long as the properties of the sol are not impaired. Examples of such additives include amino acids and triphenylphosphine.

2) Manufacturing Method The sol of the present invention can be obtained by mixing c) with a gel obtained by mixing a) and b) and transferring it to the sol. The above-described method is preferably used for mixing, and similarly, it is preferable to irradiate ultrasonic waves when mixing. Although the time for irradiating the ultrasonic wave depends on the amount of the system (mixed system of the compound and the organic solvent having a polar group), when the entire system is 1 to 10 ml, it is preferable to irradiate for 5 to 10 minutes.
The sol obtained by this production method is referred to as “virgin sol”.

  The sol of the present invention may be obtained by mixing a) to c). The mixing method is not particularly limited, but it is preferably performed by the method described above.

When the sol of the present invention further contains d) in a) to c), it can be obtained by the following method.
(I) Method of preparing gel containing components a) to d) and further mixing c) With this, it is preferable that the mixing is performed by irradiating ultrasonic waves under the conditions as already described. The mixing amount of c) is 0.8 to 5 molar equivalents, more preferably 1.1 to 3 molar equivalents relative to a) as described above.
Although the process of preparing the gel which consists of said a) -d) is not specifically limited, It is suitable to prepare with the method described in the preceding clause.

(Ii) Method of Regenerating Virgin Sol The sol of the present invention can be obtained by mixing d) with the virgin sol and transferring it to a gel, and further mixing c) to regenerate the sol. This case is referred to as “one-time regeneration sol”. The amount of d) mixed at this time is preferably 0.8 molar equivalents or more, more preferably 1 to 2 molar equivalents, relative to c) anions in the virgin sol, as already described. Further, the amount of c) to be mixed is as described above.

D) and c) may be mixed in the same manner as the once-regenerated sol to obtain a regenerated sol multiple times. The number of regenerations is not particularly limited, but is preferably 1 to 3 times because of the solubility of each component in the gel. In this case, the preferred ratio of each component of the sol is as follows.
In the case of a once-regenerated sol,
a) is 1 to 10% by mass, more preferably 2 to 5% by mass, based on the sum of a) and b)
c) is 0.8 to 5 molar equivalents relative to a), more preferably 1.1 to 3 molar equivalents d) is 0.8 molar equivalents or more relative to c), more preferably 1 to 2 equivalents.
In the case of 3 times regenerated gel,
Since c) is 4 times the amount of the once regenerated sol, 3.2 to 20 molar equivalents, more preferably 4.4 to 12 molar equivalents to the a) d) is 3 times the amount of the once regenerated sol. Therefore, c) 2.4 molar equivalents or more, more preferably 3 to 6 molar equivalents.

From the above, the preferred ratio of each component of the sol containing a) to d) is
a): 1 to 10% by mass, more preferably 2 to 5% by mass, based on the sum of a) and b)
c): 0.8-20 molar equivalents relative to a), more preferably 1.1-12 molar equivalents d): 0.8 molar equivalents or more relative to b), more preferably 3-6 molar equivalents is there.

3) Use etc. Since the sol obtained in the present invention can be transferred to a gel by d) mixing zinc bromide or the like, it can be applied to a drug delivery system or the like as a stimulus-responsive sol.

4). Sol-Gel Transition Method The gel of the present invention can be sol-gel transitioned by adding the above c) anion and d) zinc bromide or boron trifluoride. That is,
A) Step: a) A gel containing the compound of the present invention and b) an organic solvent having a polar group is prepared. B) Step: c) Anions are mixed with the gel and transferred to a sol. C) Step: The gel D) Zinc bromide or boron trifluoride is mixed and transferred to the gel again. D) Step: Further, B) or B) and C) can be applied to perform the sol-gel transition.

That is, by repeating A) step (gel) → B) step (sol) → C) step (gel) → B) step (sol) → C) step (gel) → B) step (sol). -Gel transition. The mixing amount of c) and d) in each step of the transfer reaction is preferably set to the amount already described. Moreover, it is preferable to use the method already described as the mixing method.
Such gels and sols can be expected to be applied to drug delivery systems and the like as stimulus response materials (intelligence materials).

Example 1: Synthesis of Compound A
1) Acetone suspension (130 ml) of metanitrophenol (manufactured by Tokyo Chemical Industry Co., Ltd., 9.4 g: 67 mmol) and potassium carbonate (manufactured by Kanto Chemical Co., Ltd., 9.3 g: 67 mmol) under an argon atmosphere in an ice bath Then, 1,3,5-tris (bromomethyl) -2,4,6-triethylbenzene (9.9 g: 22 mmol) was added. The reaction suspension was warmed to room temperature, reacted for 17 hours, and disappearance of the raw materials was confirmed by thin layer chromatography (TLC).
After concentrating the reaction solution on a rotary evaporator, the suspension added with chloroform was filtered to remove unnecessary potassium carbonate. The residue obtained by concentrating the filtrate was reprecipitated using a mixed solvent (1: 5) of methylene chloride and normal hexane. The solid obtained by filtration was dried by heating under vacuum to obtain a pure nitro compound as a white solid. The yield was 11.8 g (86% yield).
1,3,5-Tris (bromomethyl) -2,4,6-triethylbenzene was synthesized by the method described in Journal of the American Chemical Society 2004, Vol. 126, 16456-16465.

The structure of the obtained nitro compound was confirmed using NMR as follows.
¹ H-NMR Brucker AC300, (300 MHz, CDCl ₃ , 25 ° C.)
d 1.27 (t, J = 7.5 Hz, 9H), 2.84 (q, J = 7.5 Hz, 6H), 5.18 (s, 6H), 7.34 (dd, J = 1. 4, 8.4 Hz, 3H), 7.49 (t, J = 8.5 Hz, 3H), 7.89 to 7.91 (m, 6H)

¹³ C-NMR Brucker AC300, (75 MHz, CDCl ₃ , 25 ° C.)
d16.64, 23.27, 64.97, 108.60, 116.43, 122.16, 130.34, 130.52, 146.86, 149.49, 159.39

2) 1,4-dioxane solution (5 ml) of the nitro compound (500 mg: 0.8 mmol) obtained in the previous step and tin dichloride dihydrate (2.8 g: 12 mmol, manufactured by Aldrich) under an argon atmosphere After stirring at room temperature for 2 hours, the mixture was heated to 50 ° C. and further stirred for 3 hours, and disappearance of the raw materials was confirmed by thin layer chromatography (TLC). Next, the reaction solution was ice-cooled, and water was added to stop the reaction. Subsequently, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to neutralize the reaction solution, and then an insoluble solid was removed by Celite filtration. The solid was washed with ethyl acetate.
The organic layer and the aqueous layer were separated from the filtrate with a separatory funnel, and the aqueous layer was further extracted with ethyl acetate. The organic layer separated from the extract and the filtrate was mixed, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated on a rotary evaporator. The obtained residue was purified by silica gel column chromatography (SiO ₂ , Hexane / EtOAc = 1/1) to obtain an amine form as a white solid. The yield was 365 mg (yield 86%).

The obtained amine body confirmed the structure as follows using NMR.
¹ H-NMR Brucker AC300 (300 MHz, CDCl ₃ , 25 ° C.)
d 1.23 (t, J = 7.5 Hz, 9H), 2.82 (q, J = 7.5 Hz, 6H), 3.70 (s, 6H), 5.03 (s, 6H), 6 .32 to 6.36 (m, 6H), 6.46 (d, J = 8.8 Hz, 3H), 7.11 (t, J = 8.0 Hz, 3H)

¹³ C-NMR Brucker AC300 (75 MHz, CDCl ₃ , 25 ° C.)
d16.62, 23.07, 64.04, 101.84, 104.68, 108.26, 130.30, 131.24, 146.26, 147.93, 160.28

3) In an argon atmosphere, a methylene chloride solution (25 ml) of the amine compound (1.8 g: 3.4 mmol) obtained in the above step was cooled in an ice bath, and phenyl isocyanate (manufactured by Tokyo Chemical Industry Co., Ltd., 1. 2 mL: 11 mmol) was added.
The reaction suspension was warmed to room temperature, reacted for 2 days, and disappearance of the raw materials was confirmed by thin layer chromatography (TLC). Normal hexane was added to the reaction solution, and the solid was collected by filtration. This solid was washed with a mixed solvent of acetone and normal hexane (1: 5). The obtained solid was dried by heating under vacuum to obtain a pure urea compound (compound A) as a white solid. The yield was 2.4 g (yield 80%).

The structure of the obtained compound A was confirmed as follows using NMR.
¹ H-NMR Brucker AC300 (300 MHz, DMSO-d ₆ , 25 ° C.)
d 1.19 (t, J = 6.7 Hz, 9H), 2.77 (q, J = 6.7 Hz, 6H), 5.07 (s, 6H), 6.74 (d, J = 8. 1 Hz, 3H), 6.95 (t, J = 7.1 Hz, 3H), 7.03 (d, J = 8.0 Hz, 3H), 7.20-7.29 (m, 12H), 7. 44 (d, J = 8.1 Hz, 3H), 8.66 (s, 3H), 8.69 (s, 3H)

¹³ C-NMR Brucker AC300 (75 MHz, DMSO-d ₆ , 25 ° C.)
d16.29, 22.50, 63.97, 104.56, 107.76, 110.97, 118.24, 121.87, 129.79, 130.90, 139.64, 141.03, 145. 48, 152.49, 159.09

[Example 2: Synthesis of Compound B]
Under an argon atmosphere, the dichloroethane solution (5 ml) of the amine compound (100 mg: 0.19 mmol) obtained in Example 1 was cooled in an ice bath, and metatolyl isocyanate (manufactured by Tokyo Chemical Industry Co., Ltd., 80 il: 0.63 mmol). ) Was added. The reaction suspension was warmed to room temperature, reacted for 2 days, then heated to reflux for 8 hours, and disappearance of the raw material was confirmed by thin layer chromatography (TLC).
Normal hexane was added to the reaction solution, and the solid was collected by filtration. This solid was washed with a mixed solvent of acetone and normal hexane (1: 5). The obtained solid was dried by heating under vacuum to obtain 141 mg (yield 79%) of a pure urea compound (compound B) as a white solid.

The obtained compound B confirmed the structure as follows using NMR.
¹ H-NMR Brucker AC300 (300 MHz, DMSO-d ₆ , 25 ° C.)
d 1.20 (t, J = 7.4 Hz, 9H), 2.27 (s, 9H), 2.77 (q, J = 7.4 Hz, 6H), 5.08 (s, 6H), 6 .74 (dd, J = 1.9, 8.1 Hz, 3H), 6.78 (d, J = 7.5 Hz, 3H), 7.04 (t, J = 8.1 Hz, 3H), 7. 15 (t, J = 7.5 Hz, 3H), 7.20-7.28 (m, 12H), 8.58 (s, 3H), 8.68 (s, 3H)

¹³ C-NMR Brucker AC300 (75 MHz, DMSO-d ₆ , 25 ° C.)
d16.27, 21.21, 23.94, 63.95, 104.46, 107.76, 110.70, 115.41, 116.72, 122.60, 128.61, 129.72, 130. 68, 137.93, 139.53, 141.05, 145.45, 152.43, 159.08

[Comparative Example 1: Synthesis of Comparative Compound C]
Under an argon atmosphere, the methylene chloride solution (8 ml) of the amine compound (200 mg: 0.38 mmol) obtained in Example 1 was cooled in an ice bath, and cyclohexyl isocyanate (manufactured by Tokyo Chemical Industry Co., Ltd., 0.16 ml: 1). .25 mmol) was added.
The reaction suspension was warmed to room temperature, reacted for 7 days, and disappearance of the raw materials was confirmed by thin layer chromatography (TLC). Normal hexane was added to the reaction solution, and the solid was collected by filtration. This solid was washed with a mixed solvent of acetone and normal hexane (1: 5). The obtained solid was dried by heating under vacuum to obtain a pure urea compound (Compound C) as a white solid. The yield was 257 mg (75% yield).

The obtained compound C confirmed the structure as follows using NMR.
¹ H-NMR Brucker AC300 (300 MHz, DMSO-d ₆ , 25 ° C.)
d 1.16-1.18 (m, 15H), 1.23-1.31 (m, 6H), 1.52 (br, 6H), 1.62 (br, 6H), 1.78 (br 6H), 2.73 (q, J = 6.2 Hz, 9H), 3.45 (br, 3H), 5.02 (s, 6H), 6.05 (d, J = 7.8 Hz, 3H) ), 6.63 (d, J = 8.1 Hz, 3H), 6.90 (d, J = 7.8 Hz, 3H), 7.14 (t, J = 8.1 Hz, 3H), 7.21 (S, 3H), 8.32 (s, 3H)

¹³ C-NMR Brucker AC300 (75 MHz, DMSO-d ₆ , 25 ° C.)
d16.29, 22.50, 63.97, 104.56, 107.76, 110.97, 118.24, 121.87, 129.79, 130.90, 139.64, 141.03, 145. 48, 152.49, 159.09

[Comparative Example 2: Synthesis of compound of formula (4)]
This comparative compound was synthesized by the method described in Chemistry--A European Journal 1999, Vol. 5, 937-950. Specifically, it was synthesized as follows.
To a solution of 1S, 2S-1,2-cyclohexanediamine (manufactured by Wako Pure Chemical Industries, Ltd., 571 mg, 5 mmol) in toluene (manufactured by Kanto Chemical Co., Inc., 85 mL), dodecylisocyanic acid (manufactured by Aldrich, 2.6 mL, 11 mmol). In addition, the mixture was stirred at room temperature for 2 days and then stirred at 100 ° C. for 2 hours. After cooling the reaction solution to room temperature, a solid was obtained by suction filtration. Methylene chloride (manufactured by Kanto Chemical Co., 100 mL) was added to the obtained solid to form a suspension, and the mixture was stirred at room temperature for 12 hours, and then the solid was subjected to suction filtration. Diethyl ether (manufactured by Kanto Chemical Co., 100 mL) was added to the obtained solid to form a suspension, and the mixture was stirred at room temperature for 12 hours, and then the solid was subjected to suction filtration. The obtained solid was dried by heating under vacuum to obtain a pure urea compound as a white solid. The yield was 2.5 g (94% yield).

[Example 3]
1 ml of an organic solvent having a polar group shown in Table 1 was poured into a screw tube, and Compound A obtained in the synthesis example was added, and ultrasonic waves (ultrasonic cleaner B2510J-DTH Branson, frequency 42 kHz, 125 W) were added. Were mixed by irradiation for 5 minutes, and a gelation test was conducted. Specifically, the minimum concentration required for gelation (minimum gelation concentration: mass%) is determined by determining the presence or absence of gelation when various amounts of the above compounds are mixed with various solvents. Asked. Gelation was judged by whether or not the solvent flowed down when the screw tube was turned upside down, and the point at which it did not flow down was judged as gelation.
A gelation test was similarly conducted for Compound B.

Table 1 shows the minimum gelation concentration (% by mass) for various solvents. It was confirmed that the compound of the present invention can be efficiently gelled by mixing a small amount with various solvents.
Furthermore, when the obtained gel was stored for several months, no change was observed in its shape.

[Example 4]
The tetrabutylammonium salt of various anions shown in Table 2 was added to 565 mg (acetone gel) 565 mg (acetone 554 ml, compound A 11.3 mg) using the acetone obtained in Example 1 as a solvent, and 5 ultrasonic waves were added. Irradiated for 1 minute to perform a sol-formation test. Specifically, various amounts of the salt were mixed with acetone gel to determine the minimum concentration (minimum solation concentration) necessary for solification. The sol formation was judged based on the state that the gel became a completely homogeneous solution containing no solid. The point that became the state according to that was judged as quasi-sol formation.
The minimum solubilization concentration was represented by a value (molar equivalent with respect to the compound) obtained by dividing the number of moles of anions used for solation by the number of moles of the compound in the acetone gel. Since compound A in the acetone gel is 11.3 mg (12.8 μmol), for example, in tetrabutylammonium fluoride (Bu ₄ NF), 3.3 mg corresponds to 1 molar equivalent.
Table 2 shows the minimum solubilization concentration (molar equivalent) when various anions are used. It was confirmed that the organogel was transferred to the organosol by the addition of the anion.

[Example 5]
Boron trifluoride diethyl ether complex (BF ₃ · OEt ₂ ) (manufactured by Kanto Chemical Co., Inc.) was added to 569 mg of acetone sol containing Bu ₄ NF obtained in Example 4 so as to be 1 molar equivalent of Bu ₄ NF. Then, an ultrasonic wave was irradiated for 5 minutes and mixed to perform a regelation test. Since Bu ₄ NF in the acetone gel was 3.6 mg (14 μmol), 2.0 mg (14 μmol) of boron trifluoride diethyl ether complex was used. As a result, regelation was confirmed.
Similarly, zinc bromide (manufactured by Tokyo Chemical Industry Co., Ltd.) was added in place of BF ₃ · OEt ₂ so as to be 1 molar equivalent to Bu ₄ NF in acetone gel (3.2 mg as zinc bromide). ) When a regelation test was performed, regelation was confirmed.

[Example 6]
A sol-gel transition test was performed in the following steps.
First step: 565 mg of acetone gel obtained in Example 1 (554 ml of acetone, 11.3 mg of compound A), 3.6 mg of tetraammonium fluoride (Bu ₄ NF) (14 μmol: 1 with respect to compound A in the acetone gel) .1 molar equivalent) was added and sonicated for 5 minutes to form a sol. Next, 2.0 mg of BF ₃ · OEt ₂ (14 μmol: 1.1 molar equivalent to Bu ₄ NF in acetone gel) was added to the sol, and the mixture was irradiated with ultrasonic waves for 5 minutes for regelation.
Second step: Further, 3.6 mg of Bu ₄ NF was added in the same manner, followed by 2.0 mg of BF ₃ in the same manner.
Third step: Further, 3.6 mg of Bu ₄ NF was added in the same manner, followed by 2.0 mg of BF ₃ in the same manner.
Fourth step: Further, 3.6 mg of Bu ₄ NF was added in the same manner, followed by 2.0 mg of BF ₃ in the same manner.
As shown in Table 3, it was confirmed that the sol-gel transition occurred repeatedly.

[Comparative Example 3]
5 mg of the compound of formula (4) was mixed with 1 ml of acetone and irradiated with ultrasonic waves, but no gel was obtained. In addition, the mixture was similarly heated to 60 ° C. and then cooled, but no gel was obtained.

[Comparative Example 4]
5 mg of the compound of the formula (4) was mixed with 1 ml of DMSO, heated to 120 ° C. and then cooled to prepare a gel. Subsequently, using a DMSO gel, a sol formation test was performed in the same manner as in Example 4. However, no sol formation occurred.

[Comparative Example 5]
Comparative compound C and acetone were mixed and gelation was attempted under the same conditions as in Example 1. However, gelation did not occur.

  Since the (thio) urea compound of the present invention has a plurality of functional groups such as urea groups or thiourea groups, it is useful in various applications such as pharmaceuticals, pharmaceutical intermediates, polymer raw materials, and polymer additives. In particular, it is suitably used as a gelling agent for organic solvents having a polar group.

Claims (7)

The urea compound or thiourea compound represented by Formula (1).

(In Formula (1),
X is an oxygen atom or a sulfur atom,
Y is an aryl group,
Z is an arylene group,
R is a hydrogen atom or an alkyl group. )   An organogel comprising the urea compound or thiourea compound according to claim 1 and an organic solvent having a polar group.   An organosol comprising the urea compound or thiourea compound according to claim 1, an organic solvent having a polar group, and an anion. Mixing the urea compound or thiourea compound according to claim 1 and an organic solvent having a polar group;
Irradiating the mixture with ultrasonic waves,
The manufacturing method of the organogel containing. Preparing the organogel according to claim 2;
Mixing anions with the organogel,
The manufacturing method of the organosol containing this. Preparing an organosol according to claim 3;
Mixing zinc bromide or boron trifluoride with the organosol,
The manufacturing method of the organogel containing. A) Step of preparing the organogel according to claim 2 B) Step of mixing the anion with the anionic gel and transferring it to the organosol C) Mixing the gel with zinc bromide or boron trifluoride, and again into the organogel Step of transferring D) Further, B) or B) and C) steps.