JP6951827B2 - Menthol derivative-containing composition - Google Patents

Description

The present invention relates to compositions containing menthol derivatives.

Menthol has traditionally been used in various fields. Menthol acts on the blood vessel center and exhibits a vascular relaxing effect, so it is used as a raw material for patches, and also has an antibacterial effect, so it can be used as an antibacterial agent, skin cleanser, hair cleanser, and oral liquid. It's being used. In addition, it has a refreshing effect, prevents colds, and has the effects of heat dissipation and antipyretic, so it is a drug aimed at healing itching when bitten by insects, pain such as arthritis and neuralgia, tuberculosis, and gastrointestinal disorders. , Used in quasi-drugs, food compositions, etc. Further, as various cosmetics, bath salts, hair cleansers, and oral liquids, there is a great demand mainly for obtaining a refreshing sensation. These are mainly applied for internal use (for oral ingestion), hulls, hair or mucous membranes. Therefore, menthol is generally provided as an aqueous composition.

However, menthol is sparingly soluble in water. For the purpose of imparting water solubility to menthol, it has been proposed to convert it into, for example, menthyl lactate, menthyl glyceryl ether, tartaric acid monomenthol esters, and the like (Patent Document 1). In addition, there has been a technique for incorporating a trisodium citrate salt or the like in cosmetics or the like (Patent Documents 2 to 5).

Japanese Unexamined Patent Publication No. 2005-194243 Japanese Unexamined Patent Publication No. 2012-167053 Japanese Unexamined Patent Publication No. 2012-25746 Japanese Unexamined Patent Publication No. 2003-40724 Japanese Unexamined Patent Publication No. 2003-2810

Considering the usefulness of menthol, it is expected to further improve the water solubility and the stability of the aqueous solution while enjoying the refreshing sensation of menthol. An object of the present invention is to provide a menthol derivative-containing composition having further excellent stability of an aqueous solution.

（但し、Ｒはそれぞれ独立に水素原子又は炭素数１〜６のアシル基であり、Ｘ及びＹはそれぞれ独立に水素原子又はヒドロキシル基である。）のいずれかで表されるメントール誘導体あるいはそのアルカリ金属塩又はアルカリ土類金属塩、並びに、（Ｂ）クエン酸金属塩、を含有させてなる組成物。
［２］上記（Ｂ）のクエン酸金属塩がクエン酸のアルカリ金属塩である［１］の組成物。
［３］上記（Ｂ）のクエン酸金属塩がクエン酸のナトリウム塩である［１］の組成物。
［４］上記（Ｂ）のクエン酸金属塩がクエン酸三ナトリウムである［１］の組成物。
［５］１重量部の上記（Ａ）のメントール誘導体あるいはそのアルカリ金属塩又はアルカリ土類金属塩メントール誘導体と、０．０１〜０．２重量部の上記（Ｂ）のクエン酸金属塩と、を含有させてなる［１］〜［４］の組成物。As a result of diligent studies by the present inventors, the present invention having the following contents has been completed.
[1] (A) The following general formulas (1) to (3)

(However, R is independently a hydrogen atom or an acyl group having 1 to 6 carbon atoms, and X and Y are independently hydrogen atoms or hydroxyl groups, respectively.) A menthol derivative represented by either of them or an alkali thereof. A composition comprising a metal salt or an alkaline earth metal salt, and (B) a metal citrate salt.
[2] The composition of [1], wherein the metal salt of citric acid in (B) above is an alkali metal salt of citric acid.
[3] The composition of [1], wherein the metal salt of citric acid in (B) is a sodium salt of citric acid.
[4] The composition of [1], wherein the metal citrate salt of (B) is trisodium citrate.
[5] 1 part by weight of the menthol derivative of (A) or an alkali metal salt or alkaline earth metal salt menthol derivative thereof, and 0.01 to 0.2 parts by weight of the citrate metal salt of (B). The compositions of [1] to [4] comprising.

According to the present invention, a composition containing a menthol derivative for obtaining an aqueous solution having excellent stability can be obtained. The compositions of the present invention are applicable to conventional menthol applications. By containing the metal citrate salt, there is an advantage that an aqueous solution with less turbidity can be obtained, and when it is used as a cosmetic, it is not sticky and the slippery feeling on the skin is improved.

The composition according to the present invention contains the menthol derivative (A), an alkali metal salt or an alkaline earth metal salt thereof, and (B) a metal citrate salt.

In the present invention, the menthol derivative is a compound represented by any of the above general formulas (1) to (3). R in the general formulas (1) and (2) independently represent a hydrogen atom or an acyl group having 1 to 6 carbon atoms. When R is a hydrogen atom, it forms a hydroxyl group together with an adjacent oxygen atom, and when R is an acyl group, it can be interpreted as a protecting group against the hydroxyl group. Examples of the acyl group having 1 to 6 carbon atoms include an acetyl group and a pivaloyl group.

X and Y in the above general formula (3) are hydrogen atoms or OH groups. Both X and Y may be the same functional group or may be different from each other.

When both X and Y are OH groups in the general formula (3), it is described as the following general formula (3A).

When both X and Y are hydrogen atoms in the general formula (3), they are described as in the following general formula (3B).

The menthol derivative represented by any of the above general formulas (1) to (3) may be a free acid, an alkali metal salt, or an alkaline earth metal salt. .. When a plurality of carboxylic acids are contained in the molecule, they may form a monovalent salt or a divalent salt. Mutual conversion between salt and free acid is possible by acid treatment, salt treatment, or the like.

As will be demonstrated by Examples described later, these menthol derivatives and their salts can be used by dissolving them in water to enjoy the refreshing sensation of menthol. Therefore, it can be applied to applications in which menthol is used, such as pharmaceuticals, cosmetics and foods. The concept of cosmetics includes functional skin cosmetics, and more specifically, for example, a composition for skin cleansing.

When producing the composition of the present invention, the main synthetic route is to subject a citric acid anhydride derivative having a predetermined chemical structure and menthol to an esterification reaction.

The citric acid anhydride derivative preferably used in the present invention is a compound obtained by protecting the hydroxyl group of citric acid anhydride with an acyl group. Specifically, it is represented by the following general formula (4).

In the general formula (4), Y is a hydrogen atom or a hydroxyl group as in the case of the general formula (3) described above. Z ₁ is a hydrogen atom or a hydroxyl group like X in the general formula (3), or is −CH ₂ CO ₂ H. Z ₂ is a hydrogen atom or OR'(where R'is an acyl group having 1 to 6 carbon atoms). Hereinafter, some examples of the general formula (4) will be given.

In the general formula (4), when Y is a hydrogen atom, Z ₁ is -CH ₂ CO ₂ H, and Z ₂ is OR', it can be described as in the following general formula (4A). can. The compound of the general formula (4A) is useful for producing the compound of the general formula (1) or (2) described above.

Here, OR'can be evaluated as having a hydroxyl group protected with an acyl group having 1 to 6 carbon atoms. Protection with an acyl group is obtained by using known acylating agents such as acid anhydrides and acid halides. More specifically, by allowing an acylating agent to act on citric acid, cyclization of citric acid and protection of hydroxyl groups can usually be performed in one step. For example, it is preferable to allow an acylating agent to act on citric acid in an amount of about 3 to 5 mol times. An acid catalyst may be used in obtaining the citrate anhydride derivative, and either Lewis acid or Bronsted acid can be used as such an acid catalyst. Specific examples thereof include inorganic acids such as hydrochloric acid and sulfuric acid; and blended acids such as organic acids such as p-toluenesulfonic acid.

The solvent for obtaining the citric acid anhydride derivative is not particularly limited, and examples thereof include hydrocarbon solvents such as toluene and heptane, which can be mixed and used.

In order to obtain the compound of the general formula (1) or (2) from the compound of the general formula (4A), the citric acid anhydride derivative (4A) and the menthol (M) are subjected to an esterification reaction. Menthol is 2-isopropyl-5-methylcyclohexanol, and various steric isomers of this compound are known. In the present invention, the three-dimensional structure (arrangement) is not particularly limited. From the viewpoint of availability and cost, L-menthol is preferable.

The esterification reaction is usually carried out in a solvent, optionally in the presence of an acid or base. As an example, the scheme in which the above R'is an acetyl group (Ac) and the reaction is carried out in the presence of a sodium salt is described below. In this case, R in the general formulas (1) and (2) is an acetyl group (Ac). That is, R in the general formulas (1) and (2) is derived from R'in the general formula (4A).

By the reaction of menthol (M) and the citric acid anhydride derivative (4A'), the hydroxyl group of menthol and one of the carbonyl groups of the acid anhydride of the citric acid anhydride derivative undergo a dehydration reaction and the citric acid anhydride derivative. Opens. Depending on the carbonyl group to be reacted, a menthol derivative having the above chemical structures (1A) and (2A) is produced, and a mixture of both is usually obtained. In this reaction, it is preferable to use about 1 to 2 mol of the citric acid anhydride derivative with respect to 1 mol of menthol.

The acid catalyst that may be used in this reaction is a protonic acid such as sulfuric acid, phosphoric acid or p-toluenesulfonic acid; or an acid such as Lewis acid such as aluminum chloride or zinc chloride that is used in a normal esterification reaction. Can be mentioned. Examples of the base catalyst that may be used include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium acetate and ammonium acetate; and metal alkoxides such as sodium methoxydo and sodium ethoxydo. Class; Alternatively, bases such as those used in ordinary esterification reactions such as amines such as triethylamine and diisopropylethylamine can be mentioned.

The solvent used in this reaction is not particularly limited as long as it dissolves the raw material and does not interfere with the reaction. Specific examples include ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane, hexane, heptan, octane, cyclohexane, methylcyclohexane and ethylcyclohexane. Alternatively, halogenated hydrocarbons such as carbon tetrachloride, chloroform, methylene chloride, chloroethane, dichloroethane, propyl chloride, butyl chloride and the like can be mentioned.

The amount of solvent used in this reaction is not particularly limited. The reaction temperature is usually 0 ° C. or higher, preferably 15 ° C. or higher, and more preferably 40 ° C. or higher. From the viewpoint of suppressing the by-production of impurities, the temperature is usually 150 ° C. or lower, preferably 120 ° C. or lower.

The reaction time cannot be unconditionally defined because it depends on the substrate, reaction temperature, amount of reagent added, etc., but the reaction is generally completed in 0.1 to 20 hours. At this time, samples of the reaction mixture can be sequentially taken and analyzed by thin layer chromatography, liquid chromatography, or the like to confirm the progress of the reaction.

The menthol derivative thus obtained has a protecting group for the hydroxyl group. This protecting group is derived from the R'group in the general formula (4A) of the citric acid anhydride derivative. The menthol derivative having this protecting group is a form of the menthol derivative that can be used in the present invention. A menthol derivative having a hydroxyl group can also be obtained by deprotecting by the method described later.

In the above esterification reaction, for example, as in the above general formulas (1) and (2) (specific examples are the above chemical formulas (1A) and (2A)), a mixture of compounds having different dehydration condensation points is obtained. The method for separating the desired compound from the mixture is not particularly limited. As an example, each can be separated and purified by performing column chromatography using ODS (octadecyllsil) as a filler.

When the acyl group is finally removed by deprotection, the above-mentioned separation may be performed prior to the deprotection, or the deprotection may be performed first and then the separation may be performed.

In the above general formula (4), when Z ₁ is a hydrogen atom or a hydroxyl group like X in the above general formula (3) and Z ₂ is a hydrogen atom, the general formula (4) is as follows. It can be described as the general formula (4B). The compound of the general formula (4B) is useful for producing the compound of the general formula (3) described above.

When X or Y is a hydroxyl group, a protecting group such as an acyl group may be bonded. For example, protection with acyl groups can be obtained by using known acylating agents such as acid anhydrides and acid halides.

The acid anhydride and menthol are subjected to an esterification reaction to obtain a compound of the general formula (3). As the conditions for the esterification reaction between the acid anhydride and menthol, the above-mentioned conditions for obtaining the compound of the general formula (1) or (2) can be appropriately adopted.

For the conversion of the menthol derivatives in the general formulas (1) to (3) with free acids, alkali metal salts and alkaline earth metal salts, known methods can be appropriately referred to. When obtaining a free acid, it is usually mentioned to dissolve or suspend an alkali metal salt and / or an alkaline earth metal salt in a liquid medium and acidify the alkali metal salt and / or an alkaline earth metal salt. The liquid medium in this case is water; an aliphatic ether such as MTBE (methyl tertiary butyl ether), di-n-butyl ether, di-i-propyl ether, di-n-propyl ether, diethyl ether and the like. Ethers; esters of aliphatic carboxylic acids such as methyl acetate, ethyl acetate, butyl acetate or 3-methoxybutyl ester of acetate; acetone, methyl ethyl ketone, methyl propyl ketone (2-pentanone), methyl isopropyl ketone, 3-pentanone, Ketones such as methylisobutylketone, methylbutylketone (2-hexanone) or 3-hexanone; aromatic hydrocarbons such as benzene, toluene and xylene; pentane, hexane, heptan, octane, cyclohexane, methylcyclohexane, ethylcyclohexane and the like. Hydrocarbons of the above; or halogenated hydrocarbons such as carbon tetrachloride, chloroform, methylene chloride, chloroethane, dichloroethane, propyl chloride, butyl chloride and the like. These solvents may be used alone or in combination of two or more. Acids used to obtain free acids include mineral acids, especially non-oxidizing mineral acids or organic acids with sufficient acidity, such as sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid and / or hydroiodide, Examples include formic acid, halogenated or non-halogenated acetic acid, aliphatic or aromatic sulfonic acids. These acids may be used alone or in admixture of two or more.

When the acyl group is finally removed by deprotection and the free acid is obtained from the alkali metal salt or the alkaline earth metal salt, the order of the removal of the acyl group and the acquisition of the free acid described above does not matter. ..

When removing the acyl group (deprotection), in other words, when obtaining a menthol derivative in which R is a hydrogen atom in the above general formula (1) or (2), a general hydroxyl group deprotection reaction (deacyllation) It can be carried out according to the chemical reaction). Specifically, it is usually deacylated with an inorganic base such as potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, lithium hydroxide or an organic base such as triethylamine or tri-n-propylamine. It can be performed.

As the reaction solvent in the deprotection reaction, a ketone solvent (acetone, methyl ethyl ketone, diethyl ketone, etc.), an amide solvent (formamide, N, N-dimethylformamide, N, N-diethylacetamide, etc.), an alcohol solvent (methanol, A polar solvent such as ethanol, propanol, etc.), water, or a mixed solvent thereof is preferably used. As the reaction temperature, a range from 0 ° C. to the boiling point of the solvent can be arbitrarily adopted. The reaction time can be appropriately set according to the substrate, the reaction temperature, the amount of the reagent added, and the like, and examples thereof include about 0.1 to 20 hours. During the reaction, samples of the reaction mixture may be sequentially taken and analyzed by thin layer chromatography, liquid chromatography or the like to confirm the progress of the reaction.

As described above, the composition of the present invention further contains (B) a metal citrate salt. The type of salt in the metal citrate salt is not particularly limited, and is preferably an alkali metal salt or an alkaline earth metal salt. Among the alkali metal salts, sodium salts are preferable. One or two of the three carboxyl groups of citric acid may exist as an acid that does not form a salt, or all three carboxyl groups may be metal salts. Preferably, the metal citrate salt is trisodium citrate.

By containing the menthol derivative of (A), its alkali metal salt or alkaline earth metal salt together with the citrate metal salt, it becomes easy to dissolve in a solvent such as water, and as a result, the solution becomes cloudy for a long period of time. It can be prevented and high transparency can be maintained for a long period of time. In the absence of citrate metal salt, menthol derivatives such as citrate menthol ester, tartrate menthol ester and succinic acid menthol ester, or their alkali metal salts or alkaline earth metal salts are turbid when attempted to dissolve in water. May cause. As a result of examining this cloudiness phenomenon, the present inventors have found that citric acid, tartaric acid, and succinic acid are removed from the menthol derivative. It is presumed that white turbidity occurs because the liberated citric acid, tartaric acid, succinic acid and the metal form a salt. Therefore, even a metal salt of a menthol derivative (sodium salt, etc.) that is difficult to dissolve can be easily dissolved in a solvent such as water by using a metal citrate salt. In addition, since it is easily dissolved in a solvent such as water, when it is used as a cosmetic, it has the effect of not being sticky and improving the slippery feeling on the skin.

According to the present invention, 0.01 to 0.2 parts by weight of the citrate metal of (B) above with respect to 1 part by weight of the menthol derivative of (A) above, its alkali metal salt or alkaline earth metal salt. The salt is contained in the composition. "Contains" means that the composition is prepared by mixing the menthol derivative of (A), its alkali metal salt or alkaline earth metal salt, and the citrate metal salt of (B) by some means. Means to get. In the composition, each of the above chemical species (A) and (B) may undergo salt exchange or the like. If the content ratio of the menthol derivative of (A), its alkali metal salt or alkaline earth metal salt, and the citrate metal salt of (B) is within the above range, the characteristics as a menthol derivative are exhibited. Achieves both improved solubility at a high level.

The specific means for containing the menthol derivative of (A), its alkali metal salt or alkaline earth metal salt, and the citrate metal salt of (B) is not particularly limited. For example, the menthol derivative (A), its alkali metal salt or alkaline earth metal salt may be isolated and then mixed with the citrate metal salt, or the menthol derivative, its alkali metal salt or alkaline earth metal. A metal citrate salt may be added to the salt-containing solution or suspension.

The present invention will be described in more detail below by giving examples. The present invention is not limited to these examples.

First, the following compounds were prepared.
Compound 1: Sodium salt compound of the above general formula (1) (where R is a hydrogen atom) 2: Potassium salt compound of the above general formula (1) (where R is a hydrogen atom): Above Sodium salt compound of the general formula (2) (where R is a hydrogen atom) 4: Potassium salt compound of the above general formula (2) (where R is a hydrogen atom) 5: The above general formula (3) ) (However, X and Y are both hydrogen atoms.) Sodium salt compound 6: The potassium salt of the above general formula (3) (where X and Y are both hydrogen atoms).

In the following description, "part" means "part by weight" unless otherwise specified.
In the production of compounds 1 to 6, first, the corresponding acid anhydride derivative was produced, and the obtained acid anhydride derivative was reacted with menthol. If necessary, salt was subsequently formed and separation work was performed. The details are as follows.

In the production of compounds 1 to 4, first, a citric acid anhydride derivative was produced.
To a four-necked flask under a nitrogen atmosphere, 150 parts of toluene, 33 parts of citric acid, and 56 parts of acetic anhydride were added, and the mixture was stirred at room temperature for 30 minutes to obtain a reaction solution. The amount of acetic anhydride with respect to 1 mol of the citric acid is 2.5 mol. 2.5 parts of 95% sulfuric acid was added dropwise to this reaction solution. Then, the mixture was stirred at 80 ° C. for 2 hours. Next, 70 parts of heptane and 60 parts of toluene were added to this reaction solution, and then the mixture was cooled to 0 ° C. After keeping the temperature at 0 ° C. for 1 hour, the reaction solution was filtered to separate the solid matter. The obtained solid was washed with 50 parts of heptane and 200 parts of toluene. The solid was dried under reduced pressure at 50 ° C. for 6 hours to obtain 16 parts of the citric acid anhydride derivative represented by the chemical formula (4A') above. The school annex data for this derivative were as follows.

^{1 H-NMR (300MHz, D} 2 O): δ2.11 (2H, s, OCCH 2 C), 2.16 (3H, s, OCOMe 2), 3.22 (2H, s, CH 2 COOH).
¹³ C-NMR (300 MHz, D ₂ O): δ20.01 (OCOMe), 39.22 (CH ₂ COO), 40.28 (CH ₂ COOH), 61.99 (COCOMe), 166.1 (OCOCH ₂₎ ), 170.0 (OCOC), 172.5 (OCOME), 173.5 (COOH).

Then, a menthol derivative was synthesized.
To a four-necked flask under a nitrogen atmosphere, 200 parts of toluene, 16 parts of L-menthol, and 16 parts of the citric acid anhydride derivative obtained above are added, and the mixture is stirred and refluxed for 4 hours to obtain a reaction solution. rice field. The amount of the citric acid anhydride derivative with respect to 1 mol of the menthol is 1.5 mol. After cooling this reaction solution to 25 ° C., 260 parts of an 8 mass% sodium hydrogen carbonate aqueous solution was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Then, the reaction solution was filtered to separate the solid matter. The solid was washed twice with 100 parts of toluene, washed once with 100 parts of ethyl acetate, and then dried at 50 ° C. to obtain 29 parts of powder. This synthesis can be expressed by the following reaction formula. The obtained powder is a mixture of sodium salts represented by the above chemical formulas (1A) and (2A).

Next, the acetyl group as a protecting group was eliminated as follows.
A mixture (powder) of sodium salts represented by the above chemical formulas (1A) and (2A), 360 parts of methanol, 12 parts of potassium carbonate, and 29 parts of the above powder are added to a four-necked flask under a nitrogen atmosphere. , Stirred at room temperature for 3 hours. After the reaction, the mixture was heated under reduced pressure to distill off methanol. The remaining reaction solution was filtered, and the obtained powder was washed twice with 100 parts of ethyl acetate. This synthesis can be expressed by the following reaction formula. The resulting powder is a mixture of compound 1 and compound 3.

Separation of compounds 1 and 3 was carried out as follows.
Using Wakosil 40C18 (manufactured by Wako Pure Chemical Industries, Ltd.) as a filler and acetonitrile: water = 50: 50 (pH 3.0) as an eluate, the above-mentioned mixture is separated by column chromatography and the fraction is recovered. As a result, sodium salts represented by compounds 1 and 3 were obtained, respectively.

Compound 1:
^{1 1} H-NMR (300 MHz, D ₂ O): δ0.74 (3H, d, CHMe: side chain Me of menthol ring), 0.89 and 0.92 (2 × 3H, 2 × d, CHMe ₂ : menthol Ring side chain i-Pr), 1.05 (3H, m, CHMe: menthol ring metin and methylene), 1.45 (2H, m, -CH _2- : menthol ring methylene), 1.71 ( 2H, m, -CH _2- : Methylene in the menthol ring), 1.92 (2H, m, CHCHCMe ₂ : Metin in the menthol ring and CHCHCMe ₂ ), 2.47 (2H, m, CH ₂ COONa), 2. 62 (2H, m, CH ₂ COOCH), 4.50 (1H, dt, COOCH).
¹³ C-NMR (300 MHz, D ₂ O): δ16.10 (CHMe: side chain of menthol ring Me), 20.56 (CHMe ₂ : side chain of menthol ring i-Pr), 21.91,23.45 And 26.18 (methylene of the menthol ring), 31.53 (CHCHCMe ₂ ), 34.25 (CHMe: methine of the menthol ring), 40.69 (CHCHCMe ₂ : methine of the menthol ring), 44.02 and 45. 70 (CH ₂ COOCH and CH ₂ COONa), 75.00 and 76.77 (COH and COOCH), 173.0, 177.8 and 180.1 (3 × CO).

Compound 3:
^{1 1} H-NMR (300 MHz, D ₂ O): δ0.75 (3H, d, CHMe: side chain Me of menthol ring), 0.88 and 0.92 (2 × 3H, 2 × d, CHMe ₂ : menthol Ring side chain i-Pr), 1.05 (3H, m, CHMe: menthol ring metin and methylene), 1.45 (2H, m, -CH _2- : menthol ring methylene), 1.71 ( 2H, m, -CH _2- : Methylene in the menthol ring) 1.92 (2H, m, CHCHCMe ₂ : Metin in the menthol ring and CHCHCMe ₂ ) 2.47 and 2.50 (2 x 2H, 2 x m) , 2 × CH ₂ COONa), 4.51 (1H, dt, COOCH).
¹³ C-NMR (300 MHz, D ₂ O): δ16.01 (CHMe: side chain of menthol ring Me), 20.55 (CHMe ₂ : side chain of menthol ring i-Pr), 21.81,23.28 And 25.90 (methylene of the menthol ring), 31.39 (CHCHCMe ₂ ), 34.03 (CHMe: methine of the menthol ring), 40.50 (CHCHCMe ₂ : methine of the menthol ring), 45.11 and 45. 70 (2 × CH ₂ COONa), 74.03 and 75.02 (COH and COOCH), 173.0, 174.1 and 177.0 (3 × CO).

Compounds 2 and 4 (potassium salt) were obtained by using an aqueous potassium hydrogen carbonate solution instead of the aqueous sodium hydrogen carbonate solution when preparing the menthol derivative.

In the production of the succinic acid menthol ester potassium salt and the sodium salt of the compounds 5 and 6, first, a succinic anhydride derivative was produced.
To a four-necked flask in a nitrogen atmosphere, 150 parts of toluene, 33 parts of succinic acid, and 56 parts of acetic anhydride were added, and the mixture was stirred at room temperature for 30 minutes to obtain a reaction solution. The amount of acetic anhydride with respect to 1 mol of the succinic acid is 2.5 mol. 2.5 parts of 95% sulfuric acid was added dropwise to this reaction solution. Then, the mixture was stirred at 80 ° C. for 2 hours. Next, 70 parts of heptane and 60 parts of toluene were added to this reaction solution, and then the mixture was cooled to 0 ° C. After keeping the temperature at 0 ° C. for 1 hour, the reaction solution was filtered to separate the solid matter. The obtained solid was washed with 50 parts of heptane and 200 parts of toluene. The solid was dried under reduced pressure at 50 ° C. for 6 hours to obtain 16 parts of succinic anhydride. The succinic anhydride corresponds to one in which both X and Y are hydrogen atoms in the above general formula (4B).

Then, as shown in the following scheme, succinic anhydride (4B') and menthol (M) were subjected to an esterification reaction to further form a salt with sodium ion to obtain Compound 5.

For the esterification reaction with menthol, 200 parts of toluene, 16 parts of L-menthol, and 16 parts of the succinic anhydride obtained above were added to a four-necked flask under a nitrogen atmosphere, and the mixture was stirred under reflux for 4 hours. The reaction solution was obtained. The amount of succinic anhydride with respect to 1 mol of the menthol is 1.5 mol. After cooling this reaction solution to 25 ° C., 260 parts of an 8 mass% sodium hydrogen carbonate aqueous solution was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Then, the reaction solution was filtered to separate the solid matter. The solid was washed twice with 100 parts of toluene, washed once with 100 parts of ethyl acetate, and then dried at 50 ° C. to obtain 29 parts of a powder of compound 5 (sodium salt).

In the above, a powder of compound 6 (potassium salt) was obtained by using an aqueous solution of potassium hydrogen carbonate instead of the aqueous solution of sodium hydrogen carbonate.

Compound 5 (sodium salt of succinic acid menthol ester):
_{^{1 H-NMR (300MHz, D}} 2 O): δ0.62 (3H, d, CHMe: side chain Me menthol ring), 0.76 and 0.79 (2 × 3H, 2 × d, CHMe 2: Menthol Ring side chain i-Pr), 0.94 (3H, m, CHMe: menthol ring metin and methylene), 1.35 (2H, m, -CH _2- : menthol ring methylene), 1.58 ( 2H, m, -CH _2- : menthol ring methylene) 1.77 (2H, m, -CH _2- : menthol ring methylene) 2.39 and 2.45 (2 x 2H, m, COCH ₂₎ CH ₂ CO methylene), 4.55 (1H, dt, COOCH).
_{^{13 C-NMR (300MHz, D}} 2 O): δ16.20 (CHMe: side chain Me menthol ring), 21.01 (CHMe _2: side menthol ring chain i-Pr), 22.32,23.91 And 26.55 (methylene of the menthol ring), 31.57 (CHCHCMe ₂ ), 31.73 and 32.59 ( _{methylene of COCH 2} CH ₂ CO), 34.78 (CHMe: methine of the menthol ring), 40. 99 (CHCHCMe ₂ : menthol ring methine), 75.61 (COOCH), 175.7 and 180.7 (2 × CO). The decomposition start temperature is 249 ° C. Sodium was confirmed by ICP analysis.

Compound 6 (potassium salt of succinic acid menthol ester):
_{^{1 H-NMR (300MHz, D}} 2 O): δ0.62 (3H, d, CHMe: side chain Me menthol ring), 0.76 and 0.79 (2 × 3H, 2 × d, CHMe 2: Menthol Ring side chain i-Pr), 0.94 (3H, m, CHMe: menthol ring metin and methylene), 1.35 (2H, m, -CH _2- : menthol ring methylene), 1.58 ( 2H, m, -CH _2- : menthol ring methylene) 1.77 (2H, m, -CH _2- : menthol ring methylene) 2.39 and 2.45 (2 x 2H, m, COCH ₂₎ CH ₂ CO methylene), 4.55 (1H, dt, COOCH).
_{13C-NMR (300MHz, D 2} O): δ16.20 (CHMe: side chain Me menthol ring), 21.01 (CHMe _2: side chain i-Pr menthol ring), 22.32,23.91 and 26.55 (methylene of menthol ring), 31.57 (CHCHCMe ₂ ), 31.73 and 32.59 ( _{methylene of COCH 2} CH ₂ CO), 34.78 (CHMe: methine of menthol ring), 40.99 (CHCHCMe ₂ : Methylene ring methine), 75.61 (COOCH), 175.7 and 180.7 (2 × CO). The decomposition start temperature is 289 ° C. Potassium was confirmed by ICP analysis.

Two parts of the compound obtained above, 0.2 parts of the following additive and 97.8 parts of water were mixed to prepare aqueous solutions of Examples and Comparative Examples.
Example 1: Compound 1 + monosodium citrate
Example 2: Compound 1 + disodium citrate
Example 3: Compound 1 + trisodium citrate
Example 4: Compound 2 + trisodium citrate
Example 5: Compound 3 + Trisodium Citrate Example 6: Compound 4 + Trisodium Citrate Example 7: Compound 5 + Trisodium Citrate
Example 8: Compound 6 + trisodium citrate
Comparative Example 1: Compound 1, no additive
Comparative Example 2: Compound 2, no additive
Comparative Example 3: Compound 3, no additive
Comparative Example 4: Compound 4, no additive
Comparative Example 5: Compound 5, no additive
Comparative Example 6: Compound 6, no additive
Comparative Example 7: Compound 1 + EDTA

EDTA (ethylenediaminetetraacetic acid) is a kind of metal chelate and is often used for the purpose of improving the transparency of lotion and the like.

Evaluation 1 (storage stability)
The transparency of each of the prepared aqueous solutions was evaluated after 24 hours and 48 hours under the condition of a temperature of 40 ° C. The results were as follows.

Initial 24 hours later 48 hours later
Example 1 Transparent Transparent White turbidity
Example 2 Transparent Transparent White turbidity
Example 3 transparent transparent transparent
Example 4 transparent transparent transparent
Example 5 Transparent Transparent Transparent Transparent
Example 6 Transparent Transparent Transparent Transparent
Example 7 Transparent Transparent Transparent Transparent
Example 8 transparent transparent transparent
Comparative Example 1 White turbidity White turbidity White turbidity
Comparative Example 2 Transparent cloudiness Cloudiness
Comparative Example 3 White turbidity White turbidity White turbidity
Comparative Example 4 Transparent white turbidity White turbidity
Comparative Example 5 White turbidity White turbidity White turbidity
Comparative Example 6 Transparent white turbidity White turbidity
Comparative Example 7 Transparent white turbidity White turbidity

Evaluation 2 (Applicability to skin)
For each of the above-prepared aqueous solutions, the applicability in application was judged based on the following "score of applicability to skin".
The average score of the scores of 10 people was calculated, and the ease of getting wet and spreading on the skin was evaluated based on the following criteria.

(Score of applicability to skin)
3 points: Very smooth and easy to spread. 2 points: Smoothly applied and easy to spread. 1 point: Appropriately spread and spread easily. 0 points: I do not feel the ease of spreading.
(criterion)
A (excellent): The average score is 2 points or more.
B (good): The average score is 1 point or more and less than 2 points.
C (bad): The average score is less than 1.
The results of each of the above evaluations were as follows.

Applyability to the skin
Example 1 B
Example 2 B
Example 3 A
Example 4 A
Example 5 A
Example 6 A
Example 7 A
Example 8 A
Comparative Example 1 C
Comparative Example 2 C
Comparative Example 3 C
Comparative Example 4 C
Comparative Example 5 C
Comparative Example 6 C
Comparative Example 5 C

As described above, in the examples, the stability of the aqueous solution was excellent and the applicability to the skin was excellent. From this, it is understood that the composition of the present invention exerts various effects on menthol more effectively.

The present application claims the priority of Japanese Patent Application No. 2016-191514, the contents of which are incorporated herein by reference. As described above, exemplary embodiments of the present invention have been described in detail, but various modifications and additions can be made without departing from the spirit and scope of the present invention.

Claims (4)

(A) 1 part by weight of the following general formulas (1) to (3)

(However, R is independently a hydrogen atom or an acyl group having 1 to 6 carbon atoms, and X and Y are independently hydrogen atoms or hydroxyl groups, respectively.) A menthol derivative represented by either of them or an alkali thereof. Metal salts or alkaline earth metal salts, as well as
A composition comprising 0.01 to 0.2 parts by weight of (B) metal citrate salt. The composition according to claim 1, wherein the metal citrate salt of (B) is an alkali metal salt of citric acid. The composition according to claim 1, wherein the metal citrate salt of (B) is a sodium salt of citric acid. The composition according to claim 1, wherein the metal citrate salt of (B) is trisodium citrate .