KR100320037B1 - Water-stable-form kojic acid derivatives and preparation method thereof - Google Patents

Abstract

The present invention relates to a water-stable kojic acid derivative represented by the following structural formula (I) and a method for preparing the same, wherein 3-amino-1-propanol and phosphorus oxychloride are present in an organic solvent in the presence of an organic base in an equivalent ratio of 1: 1 to 1.3. 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide and kojic acid produced by the reaction under the following reaction in an organic solvent in the presence of a base, followed by hydrolysis and crystallization with a polar organic solvent. It features.

(I)

Description

Water-stable-form kojic acid derivatives and preparation method

The present invention relates to a water-stable kojic acid derivative represented by the following structural formula (I) and a preparation method thereof. More specifically, the water stability is very excellent, and since 3-aminopropanoic acid and kojic acid are linked in the form of phosphate diester, they can be degraded by enzymes in vivo to exhibit the physiological activity of 3-aminopropaneic acid and kojic acid. A derivative of kojic acid and a method for producing the same.

(I)

Kojic acid is a substance that inhibits the activity of tyrosinase, which forms a chelate with copper ions, and plays a major role in melanin production, and kojic acid has been used in various cosmetic preparations to inhibit melanin production of kojic acid. However, Kojic acid has low stability in water phases, and there are many problems such as changing the color as well as reducing the titer in the case of long-term storage or manufacturing process when applied to cosmetics.

Therefore, in order to improve this instability of kojic acid, the inhibitory activity and physical properties were improved through derivatization thereof. However, since kojic acid is an active site of 4-position carboxyl group and 5-position hydroxy group, it is active by protecting them. Most derivatives have substituted a 2-positioned hydroxy group because it is known to inhibit. However, this has a problem in that stability improvement such as coloring is not greatly improved due to the preservation of the hydroxyl group at the 5-position.

Accordingly, the present inventors earnestly studied to develop derivatives of water-stable kojic acid for the purpose of solving the above problems of kojic acid derivatives. As a result, 3-aminopropane phosphate, which is widely used as an active ingredient of anti-aging cosmetic composition because of its excellent effect on fibroblast proliferation and collagen synthesis and skin stability, is a phosphate diester form at the 5-position of kojic acid. In connection with the present invention, it was found that the above object can be achieved and the present invention has been completed.

Accordingly, it is an object of the present invention to provide a water-stable kojic acid derivative represented by the following structural formula (I).

(Ⅰ)

Further, another object of the present invention is to provide a method for producing kojic acid described above.

The above object can be achieved by reacting 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide with kojic acid, and more specifically, a method for preparing kojic acid derivative according to the present invention. First, 2-amino-1-propanol and phosphorus oxychloride are reacted for 1 to 2 hours at an temperature of 0 to 5 ° C. in an organic solvent in the presence of an organic base in an equivalent ratio of 1: 1 to 1.3, and then 2-chlorotetrahydro It is characterized in that -2H-1,3,2-oxazaphosphorin P-oxide is prepared, which is then reacted with kojic acid in the presence of a base, hydrolyzed and crystallized with a polar organic solvent.

Hereinafter, the present invention will be described in more detail.

Method for producing a kojic acid derivative according to the present invention,

(A) 3-amino-1-propanol and phosphorus oxychloride were reacted for 1 to 2 hours at an temperature of 0 to 5 DEG C in an organic solvent in the presence of an organic base in an equivalent ratio of 1: 1 to 1.3. Producing 2H-1,3,2-oxazaphosphorine P-oxide;

(B) reacting 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide and kojic acid produced in step (A) in an organic solvent in the presence of a base;

(C) depressurizing and concentrating the filtrate obtained by filtering the reaction solution, and then adding an acid solution to the obtained residue to react and hydrolyze at a temperature of 5 to 100 ° C. for about 3 to 10 hours; And

(D) crystallizing with polar organic solvent;

Characterized in that it comprises a.

The preparation method according to the invention can be represented by the following scheme 1:

As can be seen in Scheme 1, a method for preparing a kojic acid derivative according to the present invention is described in detail as follows.

(A) 2-chlorotetrahydro- represented by the above formula (II) by stirring 3-amino-1-propanol and phosphorus oxychloride in an organic solvent for 1 to 2 hours at a temperature of 0 to 5 ° C. in the presence of an organic base. Producing 2H-1,3,2-oxazaphosphorin P-oxide; 2-Chlorotetrahydro-2H-1,3,2-oxaza phosphorin P-oxide;

In the above step, 3-amino-1-propanol and phosphorus oxychloride are preferably reacted in an equivalent ratio of 1: 1 to 1.3. If the equivalent ratio is less than 1: 1, the desired product cannot be obtained, and if it is 1: 1.3 or more, an excess of by-products are produced in addition to the desired product. Therefore, when 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide is prepared by the above-described method, an intermediate in which 3-amino-1-propanol and phosphorus oxychloride are 1: 1 bound Is produced in more than 95, and by-products of 2-amino-1-propanol and phosphorus oxychloride 2: 1 are produced in 1 or less. However, the by-products can be separated using chromatography, or easily removed by using a difference in solubility in toluene. In particular, two chlorine atoms of the three chlorine atoms in the phosphorus oxychloride molecule are substituted with two functional groups of 3-amino-1-propanol, ie, hydroxyl and amine groups, and cyclized 2-chlorotetrahydro-2H-1,3, A 2-oxaphosphorine P-oxide is produced, and the other chlorine atom is reduced in reactivity at 5 ° C. or lower and remains unsubstituted. This is because the chlorine atom of 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide is stable in a low temperature anhydrous inert solvent and is not easily substituted with 3-amino-1-propanol. Therefore, in the preparation method of the present invention, 3-amino-1-propanol and phosphorus oxychloride are reacted at a temperature of 0 to 5 ° C. for 1 to 2 hours at an equivalent ratio of 1: 1.0 to 1.3. Propanol and phosphorus oxychloride can prevent the formation of by-products reacted at 2: 1 or more, and in particular, it is not necessary to introduce ester groups or amide groups in order to protect chlorine atoms of phosphorus oxychloride. There is an advantage to reduce.

As the organic base in step (A) of the preparation method of the present invention, pyridine, triethylamine, and the like may be used, but triethylamine is preferably used.

In the method (A) of the present invention, the organic solvent may be an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethyl ether, etc., but it is preferable to use chloroform.

On the other hand, the reaction temperature is more than 2 equivalents of 3-amino-1-propanol is substituted with phosphorus oxychloride to increase the production of by-products, and the temperature of less than 0 ℃ to reduce the solubility of the reactants difficult to proceed the reaction. In this case, a temperature in the range of 0 to 5 ° C. is preferable because the content of unreacted material is increased to lower the reaction yield.

(B) reacting 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide with kojic acid in the presence of a base in an organic solvent;

As the base in step (B) of the production method of the present invention, organic bases such as pyridine and triethylamine may be used as described in step (A), and sodium, sodium hydroxide, potassium hydroxide, and the like may be used. Bases may also be used, but preference is given to using potassium hydroxide.

In the (B) step of the production method of the present invention as an organic solvent may be used an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethyl ether, and a polar solvent such as methanol ethanol, propanol, Preference is given to using methanol.

(C) concentrating the filtrate obtained by filtration of the reaction solution under reduced pressure, and then adding an acid solution to the obtained residue to react for about 3 to 10 hours at a temperature of about 5 to 100 ° C. for hydrolysis;

Hydrolysis of the residue obtained by concentrating the filtrate obtained by filtration of the reaction solution under reduced pressure in the production method according to the present invention can be hydrolyzed using an acid catalyst such as strong cation exchange resin (Amberlyst 15), hydrochloric acid or sulfuric acid, which are general hydrolysis conditions. Can be. That is, after the acid solution is added to the obtained compound (B), the P-N bond may be hydrolyzed when the mixture is heated and stirred at a temperature of 5 to 100 ° C. Therefore, it is preferable to add an acid solution to the residue obtained by concentrating the filtrate obtained by filtration of the reaction solution, and to react it for about 5 hours at a temperature of about 5 to 100 ° C., preferably 40 ° C. for hydrolysis. The pH of the acid solution is 1-5, preferably 2-4.

(D) gradually dropping the polar organic solvent to crystallize koji acid, 3-aminopropanol phosphate diester, which is a derivative of koji acid;

Although the polar organic solvent which is a precipitation solvent used by this invention is not specifically limited, For example, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, or dioxane can be used.

Derivatives of kojic acid provided by the above-mentioned manufacturing method may be used in the form of salts by neutralizing them, and specific examples thereof include alkali metal salts such as sodium and potassium; Alkaline earth metal salts such as calcium and magnesium; Amines such as triethanolamine or salts with ammonia.

Hereinafter, the preparation method of kojic acid derivative according to the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited to these examples.

[Production Example] 2-Chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide (2-Chlorotetrahydro-2H-1,3,2-oxaza phosphorin P-oxide)

34.1 mL (0.36 mol) of phosphorus oxychloride was dissolved in 400 mL of dichloromethane, and the solution was cooled to 0-5 ° C. in an ice water bath. In another vessel, 30 mL (0.39 mol) of 3-amino-1-propanol and 102 mL (0.73 mol) of triethylamine were diluted with 200 mL of dichloromethane, and the reaction solution prepared above was added dropwise for 2 hours. After the addition, the triethylammonium chloride produced was removed. The filtrate was washed with 100 ml purified water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. After concentration, toluene was added to the obtained residue to obtain a crystal. The obtained crystals were dried in vacuo to give 53 g of white solid as a reaction product, 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide.

m.p. : 79 ~ 82 ℃

IR (CHCl ₃ , cm ⁻¹ ): 3254, 1477, 1274, 1092, 1036, 996

¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.7 (m, 1H), 1.1 (m, 1H), 3.3 (m, 2H), 4.4 (m, 2H), 4.9 (br, 1H)

Example 1 Kojic acid, 3-aminopropanol phosphate diester

10 g of kojic acid was dissolved in 80 ml of methanol, and a solution of 4.3 g of potassium hydroxide in 20 ml of methanol was slowly added dropwise and stirred at room temperature for 30 minutes. At the same temperature, 11.2 g (1.1 eq) of 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide prepared in Preparation Example was slowly added dropwise. After the addition was completed, the mixture was stirred at room temperature overnight, the reaction solution was filtered and the filtrate was concentrated under reduced pressure, and then left at 0-5 ° C. overnight. The resulting solid was filtered and dried in vacuo to give the desired product [2- (hydroxymethyl) -4-oxo-4H-pyran-5-yloxy] -1,3,2-oxazaphosphorine P-oxide as a white solid. Got it.

It was dissolved in 30 ml of an aqueous solution of pH 4, and stirred for 5 hours in a 40 ℃ thermostat. 150 ml of isopropanol was added to the stirred reaction solution to obtain crystals, and the obtained crystals were dried in vacuo to yield 16 g of kojic acid and 3-aminopropanol phosphate diester as products as a pale yellow solid.

m.p. : 118 to 128 ° C (decomposition)

IR (KBr, cm ⁻¹ ): 3446, 3322, 2904, 1658, 1616, 1250, 1090, 863

¹ H-NMR (D ₂ O): δ (ppm) = 2.05 (m, 2H), 3.15 (t, 2H), 4.12 (m, 2H), 4.54 (m, 2H), 6.64 (s, 1H), 8.27 (s, 1H)

Example 2 Koji acid, 3-aminopropanol phosphate diester sodium salt

After dissolving 1 g of kojic acid and 3-aminopropanol phosphate diester obtained in Example 1 in 30 ml of purified water, an aqueous sodium carbonate solution was added thereto to pH 7. The solution was lyophilized to give kojic acid and 3-aminopropanol phosphate diester sodium salt as a white solid.

EXAMPLE 3 Koji acid and 3-aminopropanol phosphate diester potassium salt

After dissolving 1 g of kojic acid and 3-aminopropanol phosphate diester obtained in Example 1 in 30 ml of purified water, an aqueous potassium carbonate solution was added thereto to make pH 7. The solution was lyophilized to obtain kojic acid and 3-aminopropanol phosphate diester potassium salt as a white solid.

EXAMPLE 4 Koji acid and 3-aminopropanol phosphate diester calcium salt

1 g of kojic acid and 3-aminopropanol phosphate diester obtained in Example 1 was dissolved in 30 ml of purified water, and potassium hydroxide was added thereto to pH 7. The solution was lyophilized to obtain kojic acid and 3-aminopropanol phosphate diester calcium salt as a white solid.

EXAMPLE 5 Koji acid and 3-aminopropanol phosphate diester magnesium salt

1 g of kojic acid and 3-aminopropanol phosphate diester obtained in Example 1 were dissolved in 30 ml of purified water, and magnesium oxide was added thereto to pH 7. The solution was lyophilized to obtain kojic acid and 3-aminopropanol phosphate diester magnesium salt as a white solid.

Example 6 Kojic acid, 3-Aminopropanol phosphate diester triethanolamine salt

After dissolving 1 g of kojic acid and 3-aminopropanol phosphate diester obtained in Example 1 in 30 ml of purified water, 5 triethanolamine aqueous solution was added thereto to pH 7. The solution was lyophilized to obtain kojic acid and 3-aminopropanol phosphate diester triethanolamine salt as a white solid.

[Test Example 1]

2 g of each of kojic acid, 3-aminopropanol phosphate diester and kojic acid, which are the compounds of Example 1, were dissolved in 100 ml of each aqueous solution of pH 2 to pH 8, and then stored in a 50 ° C. thermostat for 3 weeks, and then colored. The change over time was observed according to the following evaluation criteria, and the results are shown in Table 1.

coloring 1 week 2 weeks 3 weeks Example 1 Kojisan Example 1 Kojisan Example 1 Kojisan pH 2 - + - + + ++ pH 3 - + - + + ++ pH 4 - - - + - ++ pH 5 - - - + - ++ pH 6 - + - + - ++ pH 7 - + + ++ + +++ pH 8 - + + ++ + +++

<Evaluation Criteria>

－: Colorless or light yellow +: coloring pigment

++: during coloring +++: coloring

As can be seen from Table 1, the compound of the present invention is very stable and high purity in the water phase, so no discoloration occurs, no precipitation is produced.

[Test Example 2]

Example 1 Compounds of kojic acid, 3-aminopropanol phosphate diester and kojic acid were dissolved in a hydrion pH 7 buffer solution at a concentration of 50 μM, respectively, and then stored in a 50 ° C. thermostat, and then at a constant time, 254 UV absorbance was measured at nm. Table 2 shows the sample residual ratio () in the sample solution.

0.5 hours 1 hours 3 hours 6 hours 24 hours 6 days 15th 21st Example 1 100 100 100 100 99.1 95.5 92.5 91.5 Kojisan 17.2 1.0 0 0 0 0 0 0

In general, the stability of the sample at dilution concentration is greatly reduced. However, as can be seen from Table 2, the compound of Example 1 is present in a stable state in a neutral aqueous solution, but the aqueous kojic acid solution is almost decomposed within 1 hour.

Kojic acid, 3-aminopropanol phosphate diester, or a salt thereof, which is a derivative of kojic acid provided by the method of the present invention, is stable in water phase and has a high purity, and thus is easy to be applied to a water product, and also an enzyme in vivo (phosphatase). Etc.), it is possible to proliferate kojic acid having melanin production and human fibroblasts, promote the synthesis of collagen fibers (collagen), and further break down into 3-aminopropane phosphate having excellent human skin stability. It may be usefully used as a raw material for the whitening and anti-aging cosmetic composition.

Claims (6)

In the method for producing a derivative of water stable kojic acid, (A) 3-amino-1-propanol and phosphorus oxychloride were reacted for 1 to 2 hours at an temperature of 0 to 5 DEG C in an organic solvent in the presence of an organic base in an equivalent ratio of 1: 1 to 1.3. Producing 2H-1,3,2-oxazaphosphorine P-oxide; (B) reacting 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine P-oxide and kojic acid produced in step (A) in an organic solvent in the presence of a base; (C) depressurizing and concentrating the filtrate obtained by filtration of the reaction solution, and adding purified water to the obtained residue to react and hydrolyze at about 5 to 100 ° C. for about 3 to 10 hours; And (D) crystallizing with polar organic solvent; Method for producing a water-stable kojic acid derivative is represented by the following Scheme 2, comprising: The kojic acid derivative according to claim 1, wherein the organic solvent used in step (A) or (C) is dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform or ethyl ether, methanol, ethanol or propanol. Manufacturing method. The method of claim 1, wherein the base used in step (A) or (C) is pyridine, triethylamine, sodium, sodium hydroxide or potassium hydroxide. The method of claim 1, wherein the polar organic solvent used in step (D) is methanol, ethanol, isopropanol, acetone, terahydrofuran, acetonitrile or dioxane. The derivative of kojic acid represented by the following structural formula (I) and its salt which were manufactured by the method of Claim 1. (I) 6. The salt of kojic acid derivative according to claim 5, wherein the salt of kojic acid derivative is selected from alkali metal salts such as sodium and potassium; Alkaline earth metal salts such as calcium and magnesium; Derivatives of kojic acid and salts thereof, which are selected from amines such as triethanolamine or salts with ammonia.